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  • 1.
    Akram, Talia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE-C)-PIEAS, Faisalabad, Pakistan.
    Fatima, Ambrin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Klar, Joakim
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Hoeber, Jan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Zakaria, Muhammad
    Tariq, Muhammad
    Baig, Shahid M.
    Schuster, Jens
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Dahl, Niklas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Aberrant splicing due to a novel RPS7 variant causes Diamond-Blackfan Anemia associated with spontaneous remission and meningocele2020Ingår i: International Journal of Hematology, ISSN 0925-5710, E-ISSN 1865-3774, Vol. 112, nr 6, s. 894-899Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Diamond-Blackfan Anemia (DBA) is a congenital pure red cell aplasia caused by heterozygous variants in ribosomal protein genes. The hematological features associated with DBA are highly variable and non-hematological abnormalities are common. We report herein on an affected mother and her daughter presenting with transfusion-dependent anemia. The mother showed mild physical abnormalities and entered spontaneous remission at age 13 years. Her daughter was born with occipital meningocele. Exome sequencing of DNA from the mother revealed a heterozygous novel splice site variant (NM_001011.4:c.508-3T > G) in the Ribosomal Protein S7 gene (RPS7) inherited by the daughter. Functional analysis of the RPS7 variant expressed from a mini-gene construct revealed that the exon 7 acceptor splice site was replaced by a cryptic splice resulting in a transcript missing 64 bp of exon 7 (p.Val170Serfs*8). Our study confirms a pathogenic effect of a novel RPS7 variant in DBA associated with spontaneous remission in the mother and meningocele in her daughter, thus adding to the genotype-phenotype correlations in DBA.

  • 2.
    Ali, Zafar
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Klar, Joakim
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Jameel, Mohammad
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Khan, Kamal
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Fatima, Ambrin
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Raininko, Raili
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Baig, Shahid
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Dahl, Niklas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Novel SACS mutations associated with intellectual disability, epilepsy and widespread supratentorial abnormalities2016Ingår i: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 371, s. 105-111Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We describe eight subjects from two consanguineous families segregating with autosomal recessive childhood onset spastic ataxia, peripheral neuropathy and intellectual disability. The degree of intellectual disability varied from mild to severe and all four affected individuals in one family developed aggressive behavior and epilepsy. Using exome sequencing, we identified two novel truncating mutations (c.2656C>T (p.Gln886*)) and (c.4756_4760delAATCA (p.Asn1586Tyrfs*3)) in the SACS gene responsible for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). MRI revealed typical cerebellar and pontine changes associated with ARSACS as well as multiple supratentorial changes in both families as likely contributing factors to the cognitive symptoms. Intellectual disability and behavioral abnormalities have been reported in some cases of ARSACS but are not a part of the characteristic triad of symptoms that includes cerebellar ataxia, spasticity and peripheral neuropathy. Our combined findings bring further knowledge to the phenotypic spectrum, neurodegenerative changes and genetic variability associated with the SACS gene of clinical and diagnostic importance.

  • 3.
    Ali, Zafar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Zulfiqar, Shumaila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Klar, Joakim
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Wikström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Ullah, Farid
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Khan, Ayaz
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Abdullah, Uzma
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Baig, Shahid
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Dahl, Niklas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Homozygous GRID2 missense mutation predicts a shift in the D-serine binding domain of GluD2 in a case with generalized brain atrophy and unusual clinical features2017Ingår i: BMC Medical Genetics, E-ISSN 1471-2350, Vol. 18, nr 1, artikel-id 144Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Spinocerebellar ataxias comprise a large and heterogeneous group of disorders that may present with isolated ataxia, or ataxia in combination with other neurologic or non-neurologic symptoms. Monoallelic or biallelic GRID2 mutations were recently reported in rare cases with cerebellar syndrome and variable degree of ataxia, ocular symptoms, hypotonia and developmental delay.

    CASE PRESENTATION: We report on a consanguineous family with autosomal recessive childhood onset of slowly progressive cerebellar ataxia and delayed psychomotor development in three siblings. MRI of an adult and affected family member revealed slightly widened cerebral and cerebellar sulci, suggesting generalized brain atrophy, and mild cerebellar atrophy. Using whole exome sequencing we identified a novel homozygous missense variant [c.2128C > T, p.(Arg710Trp)] in GRID2 that segregates with the disease. The missense variant is located in a conserved region encoding the extracellular serine-binding domain of the GluD2 protein and predicts a change in conformation of the protein.

    CONCLUSION: The widespread supratentorial brain abnormalities, absence of oculomotor symptoms, increased peripheral muscle tone and the novel missense mutation add to the clinical and genetic variability in GRID2 associated cerebellar syndrome. The neuroradiological findings in our family indicate a generalized neurodegenerative process to be taken into account in other families segregating complex clinical features and GRID2 mutations.

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  • 4.
    Angsten, Gertrud
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnkirurgisk forskning.
    Gustafson, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnkirurgisk forskning.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Christofferson, Rolf H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnkirurgisk forskning.
    Resolution of infantile intestinal pseudo-obstruction in a boy2017Ingår i: Journal of Pediatric Surgery Case Reports, E-ISSN 2213-5766, Vol. 24, s. 28-34Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A term boy with spontaneous passage of meconium exhibited episodes of abdominal distension and diarrhea. Due to failure to thrive and suspicion of Hischsprung's disease he was referred to our university hospital at five months of age. Rectal biopsies were normal. Laparotomy revealed dilation of the small bowel and colon without any mechanical obstruction. Full thickness bowel biopsies were taken and a loop ileostomy was constructed. Histopathology revealed fibrosing myopathy, Cajal cell hypertrophy, and neuronal degeneration in both the large and small bowel. The small bowel showed mastocytosis without inflammation. A central venous catheter was placed for vascular access, replaced three times and later switched to a subcutaneous venous port. Catheters were locked after use with vancomycin-heparin and later taurolidine. The individually tailored home parenteral nutrition contained unsaturated fatty acid lipids to reduce cholestasis. Initial insufficient growth was improved after correction of partial parenteral nutrition based on a metabolic balance study. The ileostomy was revised once and finally taken down at 11 years of age following one year without parenteral support. At follow-up at 13 years of age he has episodes of moderate abdominal pain and has entered puberty and reports a high quality of life. (C) 2017 The Authors. Published by Elsevier Inc.

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  • 5.
    Annerén, Göran
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Uddenfeldt, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Janols, Lars-Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Asperger syndrome in a boy with a balanced de novo translocation: t(17;19)(p13.3;p11)1995Ingår i: American Journal of Medical Genetics, ISSN 0148-7299, E-ISSN 1096-8628, Vol. 56, nr 3, s. 330s. 330-1Artikel i tidskrift (Övrigt vetenskapligt)
  • 6.
    Arnell, Henrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Hjalmas, Kelm
    Jagervall, Martin
    Läckgren, Göran
    Stenberg, Arne
    Bengtsson, Bengt
    Wassen, Christer
    Emahazion, Tesfai
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Annerén, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Pettersson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Sundvall, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    The genetics of primary nocturnal enuresis: inheritance and suggestion of a second major gene on chromosome 12q1997Ingår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 34, nr 5, s. 360-5Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Primary nocturnal enuresis (PNE), or bedwetting at night, affects approximately 10% of 6 year old children. Genetic components contribute to the pathogenesis and recently one locus was assigned to chromosome 13q. We evaluated the genetic factors and the pattern of inheritance for PNE in 392 families. Dominant transmission was observed in 43% and an apparent recessive mode of inheritance was observed in 9% of the families. Among the 392 probands the ratio of males to females was 3:1 indicating sex linked or sex influenced factors. Linkage to candidate regions was tested in 16 larger families segregating for autosomal dominant PNE. A gene for PNE was excluded from chromosome 13q in 11 families, whereas linkage to the interval D13S263-D13S291 was suggested (Zmax = 2.1) in three families. Further linkage analyses excluded about 1/3 of the genome at a 10 cM resolution except the region around D12S80 on chromosome 12q that showed a positive two point lod score in six of the families (Zmax = 4.2). This locus remains suggestive because the material was not sufficiently large to give evidence for heterogeneity. Our pedigree analysis indicates that major genes are involved in a large proportion of PNE families and the linkage results suggest that such a gene is located on chromosome 12q.

  • 7.
    Arnell, Henrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Mäntyjärvi, Maija
    Tuppurainen, Kaija
    Andreasson, Sten
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Stargardt disease: linkage to the ABCR gene region on 1p21-p22 in Scandinavian families1998Ingår i: Acta Ophthalmologica Scandinavica, ISSN 1395-3907, E-ISSN 1600-0420, Vol. 76, nr 6, s. 649-52Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Stargardt disease (STGD) or fundus flavimaculatus (FFM) is one of the most frequent causes of macular degeneration in childhood. The disease is inherited as an autosomal recessive trait and the corresponding gene has been localized to chromosome 1p21-22 and subsequently identified as the ATP-binding cassette transporter (ABCR) gene. PURPOSE: To characterize Finnish and Swedish STGD families genetically, with special reference to chromosome region 1p21-22. METHODS: We performed genetic linkage and haplotype analyses in five families of Finnish and Swedish origin with members affected by STGD or FFM. RESULTS: Evidence for linkage between STGD and the ABCR gene region on chromosome 1p was found with a maximum cumulative two-point lod score for marker D1S188 (Z=4.04, theta=0.001). The affected individuals of all families, including the offspring of a consanguineous family, were found heterozygous for haplotypes spanning the ABCR gene. CONCLUSION: The results support genetic homogeneity for a STGD/FFM gene defect on chromosome 1p21-22. A variety of haplotypes tightly linked to the ABCR gene region were found among affected individuals which indicate the presence of several independent STGD mutations in the Scandinavian population.

  • 8.
    Arnell, Henrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Nemeth, Antal
    Annerén, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Progressive familial intrahepatic cholestasis (PFIC): evidence for genetic heterogeneity by exclusion of linkage to chromosome 18q21-q221997Ingår i: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 100, nr 3-4, s. 378-381Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Progressive familial intrahepatic cholestasis (PFIC) is the second most common form of familial intrahepatic cholestasis. The genes for PFIC and for a milder form of the disease, benign recurrent intrahepatic cholestasis (BRIC), were recently mapped to a 19-cM region on chromosome 18q21-q22. The results suggest that PFIC and BRIC are allelic diseases. We have studied 11 Swedish patients from eight families with clinical and biochemical features consistent with PFIC. The families were genotyped for markers D18S69, D18S64, D18S55 and D18S68, spanning the PFIC candidate region. Unexpectedly, the segregation of haplotypes excluded the entire region in three families, and no indications for shared haplotypes were found in the patients of the six remaining families. A four-point linkage analysis of all families excluded linkage from D18S69 to D18S55 (Zmax < -5). Thus, our data strongly suggest the presence of a second, yet unknown, locus for PFIC. The results indicate that great care should be taken when using 18q markers for prenatal diagnosis and genetic counseling for the disease.

  • 9.
    Arzoo, Pakeeza Shaiq
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Klar, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Bergendal, Birgitta
    Norderyd, Johanna
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    WNT10A Mutations Account for 1/4 of Population- Based Isolated Oligodontia and Show Phenotypic Correlations2014Ingår i: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 164, nr 2, s. 353-359Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A large proportion (>50%) of patients with isolated oligodontia were recently reported with WNT10A mutations. We have analyzed a population-based cohort of 102 individuals diagnosed with non-syndromic oligodontia and a mean of 8.2 missing teeth. The cohort included 94 families and screening of WNT10A identified that 26 probands (27.7%) had at least one WNT10A variant. When we included the MSX1, PAX9, AXIN2, EDA, EDAR, and EDARADD genes, 38.3% of probands were positive for a mutation. Biallelic WNT10A mutations were strongly associated with a larger number of missing teeth (11.09) when compared to both monoallelic WNT10 mutations (6.82) and the group without mutations in WNT10A, MSX1, PAX9, AXIN2, EDA, EDAR, or EDARADD (7.77). Genotype-phenotype analysis of individuals with WNT10A mutations showed that premolars were the most common missing teeth. Furthermore, biallelic WNT10A mutations were associated with absence of maxillary and mandibular molars as well as mandibular central incisors. Maxillary central incisors were always present. Thus, our study indicates that WNT10A mutations are associated with both the type and numbers of missing teeth. Furthermore, we show that this population-based cohort of isolated oligodontia had a considerably lower frequency of mutated WNT10A alleles and a lower mean number of missing teeth when compared to patients recruited from dental specialist centers. (c) 2013 Wiley Periodicals, Inc.

  • 10. Azhar, Aysha
    et al.
    Tariq, Muhammad
    Baig, Shahid Mahmood
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Klar, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    A novel mutation in Lysophosphatidic Acid Receptor 6 gene in autosomal recessive hypotrichosis and evidence for a founder effect2012Ingår i: EJD. European journal of dermatology, ISSN 1167-1122, E-ISSN 1952-4013, Vol. 22, nr 4, s. 464-466Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mutations in the lysophosphatidic acid receptor 6 (LPAR6) gene cause localized autosomal recessive hypotrichosis. We report six consanguineous families from Pakistan with segregating hypotrichosis localized to the scalp. Genetic investigation using polymorphic microsatellite markers revealed homozygosity spanning the LAH3 locus on chromosome 13 in affected individuals of all six families. Sequence analysis of the LPAR6 gene showed a novel insertion resulting in a frameshift and a premature termination (p.I194FfsX11) in affected members of one family. In the remaining five families we identified a previously described missense mutation (p.G146R) in a homozygous state in affected members. The closest flanking polymorphic marker showed an identical allele size in the five families segregating with the p. G146R mutation, supporting a single origin of this variation. These findings extend the spectrum of known LPAR6 mutations and suggest a founder effect of the p. G146R mutation in the Pakistani population.

  • 11.
    Badhai, Jitendra
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Fröjmark, Anne-Sophie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Davey, Edward J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Ribosomal protein S19 and S24 insufficiency cause distinct cell cycle defects in Diamond-Blackfan anemia2009Ingår i: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1792, nr 10, s. 1036-1042Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Diamond-Blackfan anemia (DBA) is a severe congenital anemia characterized by a specific decrease of erythroid precursors. The disease is also associated with growth retardation, congenital malformations, a predisposition for malignant disease and heterozygous mutations in either of the ribosomal protein (RP) genes RPS7, RPS17, RPS19, RPS24, RPL5, RPL11 and RPL35a. We show herein that primary fibroblasts from DBA patients with truncating mutations in RPS19 or in RPS24 have a marked reduction in proliferative capacity. Mutant fibroblasts are associated with extended cell cycles and normal levels of p53 when compared to w.t. cells. RPS19 mutant fibroblasts accumulate in the G1 phase, whereas the RPS24 mutant cells show an altered progression in the S phase resulting in reduced levels in the G2/M phase. RPS19 deficient cells exhibit reduced levels of Cyclin-E, CDK2 and retinoblastoma (Rb) protein supporting a cell cycle arrest in the G1 phase. In contrast, RPS24 deficient cells show increased levels of the cell cycle inhibitor p21 and a seemingly opposing increase in Cyclin-E, CDK4 and CDK6. In combination, our results show that RPS19 and RPS24 insufficient fibroblasts have an impaired growth caused by distinct blockages in the cell cycle. We suggest this proliferative constraint to be an important contributing mechanism for the complex extra-hematological features observed in DBA.

  • 12.
    Badhai, Jitendra
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Fröjmark, Anne-Sophie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Gidlöf, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Differential expression of RPS19 5’UTR variants implicated in Diamond-Blackfan anemia2012Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Heterozygous mutations in the ribosomal protein (RP) S19 gene RPS19 are found in about 25% of patients with the congenital erythroblastopenia Diamond-Blackfan anemia (DBA). The RPS19 gene encodes a single RPS19 isoform from three known transcriptional start sites (TSS) with different 5’ untranslated region (UTR). The regulation of RPS19 expression is poorly understood as well as the significance of different 5’UTRs. A few rare sequence variants within the 5’UTR have also been reported in patients with DBA. We determined the transcriptional start sites (TSS) and the tissue distribution of variant 5’UTRs of RPS19. Twenty-nine novel TSS in K562 cells and testis were identified. We then analyzed the relative proportion of three selected 5’UTRs of different length on a panel of primary tissues. The shorter 5’UTR were most abundant in all tissues but with large variations in relative levels of shorter versus longer transcripts. To clarify the effect of different RPS19 5’UTRs on translation we designed and expressed constructs using three 5’UTRs of different length. The short 5’UTR(+35nt.) translate 4-6 folds more efficiently than the two longer variants with 5’UTRs of 382nt. and 467nt., respectively We also introduced DBA associated insertion (c.-149_-148insGCCA, c.-149_-148insAGCC ) and deletion (c.-144_-141delTTTC) variants in the 5’UTR. . Interestingly, the DBA associated 5’UTR sequence variants showed a 20-30% reduction in RPS19 levels when compared to the corresponding w.t. constructs. Our results indicate that the RPS19 gene has a broad range of TSS with tissue specific variations. We also show that sequence variants in the 5’UTR in some DBA patients reduce RPS19 expression with implications for the pathophysiology of the disease.

  • 13.
    Badhai, Jitendra
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Fröjmark, Anne-Sophie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Razzaghian, Hamid Reza
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Davey, Edward
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Posttranscriptional down-regulation of small ribosomal subunit proteinscorrelates with reduction of 18S rRNA in RPS19 deficiency2009Ingår i: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 583, nr 12, s. 2049-2053Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ribosomal protein S19 (RPS19) is mutated in patients with Diamond-Blackfan anemia (DBA). We hypothesized that decreased levels of RPS19 lead to a coordinated down-regulation of other ribosomal (r-)proteins at the subunit level. We show that small interfering RNA (siRNA) knock-down of RPS19 results in a relative decrease of small subunit (SSU) r-proteins (S20, S21 and S24) when compared to large subunit (LSU) r-proteins (L3, L9, L30 and L38). This correlates with a relative decrease in 18S rRNA with respect to 28S rRNA. The r-protein mRNA levels remain relatively unchanged indicating a post transcriptional regulation of r-proteins at the level of subunit formation.

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    FULLTEXT01
  • 14.
    Badhai, Jitendra
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gidlöf, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    5'UTR Variants of Ribosomal Protein S19 Transcript Determine Translational Efficiency: Implications for Diamond-Blackfan Anemia and Tissue Variability.2011Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 6, nr 3, s. e17672-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The RPS19 gene uses a broad range of TSS and a short 5'UTR is associated with increased levels of RPS19. Comparisons between tissues showed a broad variation in the total amount of RPS19 mRNA and in the distribution of TSS used. Furthermore, our results indicate that rare polymorphic 5'UTR variants reduce RPS19 protein levels with implications for Diamond-Blackfan anemia.

  • 15.
    Balciuniene, Jorune
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Borg, Erik
    Samuelsson, Eva
    Koisti, Markus J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Pettersson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Jazin, Elena E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Evidence for digenic inheritance of nonsyndromic hereditary hearing loss in a Swedish family1998Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 63, nr 3, s. 786-93Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We investigated a Swedish family with nonsyndromic progressive bilateral sensorineural hearing loss. Thirteen candidate loci for autosomal dominant nonsyndromic hearing loss were tested for linkage in this family. We found significant LOD scores (>3) for markers at candidate locus DFNA12 (11q22-q24) and suggestive LOD scores (>2) for markers at locus DFNA2 (1p32). Our results for markers on chromosome 11 narrowed down the candidate region for the DFNA12 locus. A detailed analysis of the phenotypes and haplotypes shared by the affected individuals supported the notion that two genes segregated together with hearing impairment in the family. Severely affected family members had haplotypes linked to the disease allele on both chromosomes 1 and 11, whereas individuals with milder hearing loss had haplotypes linked to the disease allele on either chromosome 1 or chromosome 11. These observations suggest an additive effect of two genes, each gene resulting in a mild and sometimes undiagnosed phenotype, but both together resulting in a more severe phenotype.

  • 16.
    Balciuniene, Jorune
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Jalonen, Paula
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Verhoeven, Kristien
    Van Camp, Guy
    Borg, Erik
    Pettersson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Jazin, Elena E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Alpha-tectorin involvement in hearing disabilities: One gene-two phenotypes1999Ingår i: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 105, nr 3, s. 211-216Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The human alpha-tectorin (TECTA) gene has recently been cloned and proposed to be involved in autosomal dominant non-syndromic hearing impairment (NSHI) in two families linked to the DFNA12 locus. We have studied a Swedish pedigree with autosomal dominant NSHI with possible digenic inheritance of the disease, involving locus DFNA12 in chromosome 11 and locus DFNA2 in chromosome 1. Mutation analysis of the TECTA gene in this family has identified eight nucleotide substitutions indicating that TECTA is highly polymorphic. One of the changes results in a cysteine to serine (C 1057 S) mutation, in the zonadhesin domain of TECTA; this segregates with the disease haplotype on chromosome 11 and is not present in a control population. The mutation results in the replacement of a cysteine in one of the repeats of the zonadhesin/Von Willebrand domain of the protein and might cause a change in the crosslinking of the polypeptide. These findings add support to the involvement of TECTA in hearing disabilities. However, the three families carrying different TECTA mutations also show phenotypic differences: the hearing loss ranges from prelingual to progressive with late onset. The explanation for the different phenotypes and some clues regarding the functions of TECTA may lie in the localization of the mutations in the different modules of the protein. Another possibility is that the phenotype in the Swedish family is the result of two defective genes.

  • 17.
    Barrio, Alvaro Martinez
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Centrum för bioinformatik.
    Eriksson, Oskar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Badhai, Jitendra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Fröjmark, Anne-Sophie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Bongcam-Rudloff, Erik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Centrum för bioinformatik.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Targeted Resequencing and Analysis of the Diamond-Blackfan Anemia Disease Locus RPS192009Ingår i: PLoS ONE, ISSN 1932-6203, Vol. 4, nr 7, s. e6172-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The Ribosomal protein S19 gene locus (RPS19) has been linked to two kinds of red cell aplasia, Diamond-Blackfan Anemia (DBA) and Transient Erythroblastopenia in Childhood (TEC). Mutations in RPS19 coding sequences have been found in 25% of DBA patients, but not in TEC patients. It has been suggested that non-coding RPS19 sequence variants contribute to the considerable clinical variability in red cell aplasia. We therefore aimed at identifying non-coding variations associated with DBA or TEC phenotypes. METHODOLOGY/PRINCIPAL FINDINGS: We targeted a region of 19'980 bp encompassing the RPS19 gene in a cohort of 89 DBA and TEC patients for resequencing. We provide here a catalog of the considerable, previously unrecognized degree of variation in this region. We identified 73 variations (65 SNPs, 8 indels) that all are located outside of the RPS19 open reading frame, and of which 67.1% are classified as novel. We hypothesize that specific alleles in non-coding regions of RPS19 could alter the binding of regulatory proteins or transcription factors. Therefore, we carried out an extensive analysis to identify transcription factor binding sites (TFBS). A series of putative interaction sites coincide with detected variants. Sixteen of the corresponding transcription factors are of particular interest, as they are housekeeping genes or show a direct link to hematopoiesis, tumorigenesis or leukemia (e.g. GATA-1/2, PU.1, MZF-1). CONCLUSIONS: Specific alleles at predicted TFBSs may alter the expression of RPS19, modify an important interaction between transcription factors with overlapping TFBS or remove an important stimulus for hematopoiesis. We suggest that the detected interactions are of importance for hematopoiesis and could provide new insights into individual response to treatment.

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  • 18. Bergendal, Birgitta
    et al.
    Klar, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Stecksén-Blicks, Christina
    Norderyd, Johanna
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Isolated Oligodontia Associated With Mutations in EDARADD, AXIN2, MSX1, and PAX9 Genes2011Ingår i: American Journal of Medical Genetics Part A, ISSN 1552-4825, Vol. 155, nr 7, s. 1616-1622Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Oligodontia is defined as the congenital lack of six or more permanent teeth, excluding third molars. Oligodontia as well as hypodontia (lack of one or more permanent teeth) are highly heritable conditions associated with mutations in the AXIN2, MSX1, PAX9, EDA, and EDAR genes. Here we define the prevalence of mutations in the AXIN2, MSX1, PAX9, EDA, and EDAR genes, and the novel candidate gene EDARADD in a cohort of 93 Swedish probands with non-syndromic, isolated oligodontia. Mutation screening was performed using denaturing gradient gel electrophoresis and DNA sequence analysis. Analyses of the coding sequences of the six genes showed sequence alterations predicted to be damaging or potentially damaging in ten of 93 probands (10.8%). Mutations were identified in the EDARADD (n = 1), AXIN2 (n = 3), MSX1 (n = 2), and PAX9 (n = 4) genes, respectively. None of the 10 probands with mutations had other self-reported symptoms from ectodermal tissues. The oral parameters were similar when comparing individuals with and without mutations but a family history of oligodontia was three times more frequent for probands with mutations. EDARADD mutations have previously been reported in a few families segregating hypohidrotic ectodermal dysplasia and this is, to our knowledge, the first report of an EDARADD mutation associated with isolated oligodontia.

  • 19.
    Bergendal, Birgitta
    et al.
    Inst Postgrad Dent Educ, Natl Oral Disabil Ctr Rare Disorders, POB 1030, SE-55111 Jonkoping, Sweden.;Jonkoping Univ, Sch Hlth & Welf, Jonkoping, Sweden..
    Norderyd, Johanna
    Inst Postgrad Dent Educ, Natl Oral Disabil Ctr Rare Disorders, POB 1030, SE-55111 Jonkoping, Sweden.;Jonkoping Univ, Sch Hlth & Welf, Jonkoping, Sweden..
    Zhou, Xiaolei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Klar, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Abnormal primary and permanent dentitions with ectodermal symptoms predict WNT10A deficiency2016Ingår i: BMC Medical Genetics, E-ISSN 1471-2350, Vol. 17, artikel-id 88Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The WNT10A protein is critical for the development of ectodermal appendages. Variants in the WNT10A gene may be associated with a spectrum of ectodermal abnormalities including extensive tooth agenesis. Methods: In seven patients with severe tooth agenesis we identified anomalies in primary dentition and additional ectodermal symptoms, and assessed WNT10A mutations by genetic analysis. Results: Investigation of primary dentition revealed peg-shaped crowns of primary mandibular incisors and three individuals had agenesis of at least two primary teeth. The permanent dentition was severely affected in all individuals with a mean of 21 missing teeth. Primary teeth were most often present in positions were succedaneous teeth were missing. Furthermore, most existing molars had taurodontism. Light, brittle or coarse hair was reported in all seven individuals, hyperhidrosis of palms and soles in six individuals and nail anomalies in two individuals. The anomalies in primary dentition preceded most of the additional ectodermal symptoms. Genetic analysis revealed that all seven individuals were homozygous or compound heterozygous for WNT10A mutations resulting in C107X, E222X and F228I. Conclusions: We conclude that tooth agenesis and/or peg-shaped crowns of primary mandibular incisors, severe oligodontia of permanent dentition as well as ectodermal symptoms of varying severity may be predictors of biallelic WNT10A mutations of importance for diagnosis, counselling and follow-up.

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  • 20. Björses, P
    et al.
    Aaltonen, J
    Vikman, A
    Perheentupa, J
    Ben-Zion, G
    Chiumello, G
    Dahl, N
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Heideman, P
    Hoorweg-Nijman, J J G
    Mathivon, L
    Mullis, P E
    Pohl, M
    Ritzén, M
    Romeo, G
    Shapiro, M S
    Smith, C S
    Solyom, J
    Zlotogora, J
    Peltonen, L
    Genetic homogeneity of autoimmune polyglandular disease type I1996Ingår i: Am J Hum Genet, Vol. 59, s. 879-886Artikel i tidskrift (Refereegranskat)
  • 21. Blomquist, H. K:son
    et al.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gustafsson, L.
    Hellerud, C.
    Holme, I.
    Holmgren, G.
    Mattsson, L.
    von Zweigberk, M.
    Glycerol kinase deficiency in two brothers with and without clinical manifestations1996Ingår i: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 50, nr 5, s. 375-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We report two brothers with glycerol kinase deficiency (GKD). The older brother had serious clinical symptoms, mental and growth retardation, abnormal skeleton, spontaneous fractures and premature loss of abnormal teeth. He and his mother had low serum phosphate levels. He had elevated serum and urine glycerol levels and GKD was found in cultured fibroblasts. Prenatal diagnosis was performed in the second pregnancy. Glycerol kinase activity was considered normal in a chorionic villus sample of the foetus. After birth, it was found that the boy had elevated serum and urine glycerol levels. Enzymatic analysis in cultured fibroblasts revealed that this boy also had GKD, in spite of having no expression of the disease. Chromosomal analyses in the parents and both boys were normal. Major rearrangements or deletions were not detected in molecular studies of DNA from the two brothers. The hybridisation pattern was normal and no allelic loss was observed.

  • 22.
    Bondeson, Marie-Louise
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Malmgren, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Kleijer, Wim J.
    Tönnesen, Tönne
    Carlberg, Britt-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Pettersson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Inversion of the IDS gene resulting from recombination with IDS-related sequences is a common cause of the Hunter syndrome1995Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 4, nr 4, s. 615-621Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have recently described the identification of a second IDS locus (IDS-2) located within 90 kb telomeric of the IDS gene (Bondeson et al. submitted). Here, we show that this region is involved in a recombination event with the IDS gene in about 13% of patients with the Hunter syndrome. Analysis of the resulting rearrangement at the molecular level showed that these patients have suffered a recombination event that results in a disruption of the IDS gene in intron 7 with an inversion of the intervening DNA. Interestingly, all of the six cases with a similar type of rearrangement showed recombination between intron 7 of the IDS gene and sequences close to exon 3 at the IDS-2 locus implying that these regions are hot spots for recombination. Analysis by nucleotide sequencing showed that the inversion is caused by recombination between homologous sequences present in the IDS gene and the IDS-2 locus. No detectable deletions or insertions were observed as a result of the recombination event. The results in this study have practical implications for diagnosis of the Hunter syndrome.

  • 23.
    Bondeson, Marie-Louise
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Malmgren, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Carlberg, Britt-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Pettersson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Presence of an IDS-related locus (IDS2) in Xq28 complicates the mutational analysis of Hunter syndrome1995Ingår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 3, nr 4, s. 219-227Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A deficiency of the enzyme iduronate-2-sulfatase (IDS) is the cause of Hunter syndrome (mucopolysaccharidosis type II). Here, we report a study of the human IDS locus at Xq28. An unexpected finding was an IDS-related region (IDS2) which is located on the telomeric side of the IDS gene within 80 kb. We have identified sequences in this locus that are homologous to exons 2 and 3 as well as sequences homologous to introns 2, 3 and 7 of the IDS gene. The exon 3 sequences in the IDS gene and in the IDS2 locus showed 100% identity. The overall identities of the other identified regions were 96%. A locus for DXS466 was also found to be located close to IDS2. The existence of the IDS2 locus complicates the diagnosis of mutations in genomic DNA from patients with Hunter syndrome. However, information about the IDS2 locus makes it possible to analyze the IDS gene and the IDS2 locus separately after PCR amplification.

  • 24. Bone, L.
    et al.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Lensch, M.
    Chance, P.
    Kelly, T.
    Le Guern, E.
    Magi, S.
    Parry, G.
    Shapiro, H.
    Wang, S.
    Fischbeck, K.
    New connexin32 muations associated with X-linked Charcot-Marie-Tooth disease1995Ingår i: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 45, nr 10, s. 1863-6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Analysis of the connexin32 gene in patients with X-linked Charcot-Marie-Tooth disease shows mutations distributed throughout the molecule, with all domains affected except the fourth transmembrane domain and the distal carboxy terminus. Sequence analysis of DNA from 19 unrelated patients detected six novel mutations and three previously reported mutations. Identification of additional mutations extends the distribution of connexin32 mutations in X-linked Charcot-Marie-Tooth disease and shows that specific mutations recur in additional families.

  • 25. Borg, Erik
    et al.
    Samuelsson, Eva
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Audiometric Characterization of a Family with Digenic Autosomal, Dominant, Progressive Sensorineural Hearing Loss2000Ingår i: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 120, nr 1, s. 51-57Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this study, a non-syndromic progressive bilateral high frequency hearing loss is described in a family with 141 identified members. Recent genetic analyses indicated a digenic inheritance with linkage to the gene loci DFNA2 and DFNA12. The affected family members who shared haplotypes at both loci (type I) showed an early postlingual onset and a more rapid rate of progress compared with those with one either of the two disease associated haplotypes (type II). The audiometric pattern was cochlear without a vestibular involvement. Auditory brainstem response audiometry and magnetic resonance imaging indicated normal retrocochlear features. The otoacoustic emissions were affected for both type I and type II, whereas the acoustic stapedius reflex thresholds were normal in most cases. It is concluded that both types had an outer hair cell/micro-mechanical abnormality, but that the DFNA 2 type might have an additional dysfunction at the level of the inner hair cells. It is furthermore pointed out that the application of refined audiometric techniques as well as a further development of new techniques is needed in order to characterize the phenotypes of the rapidly expanding number of genetically defined inner ear abnormalities.

  • 26. Boria, Ilenia
    et al.
    Garelli, Emanuela
    Gazda, Hanna T.
    Aspesi, Anna
    Quarello, Paola
    Pavesi, Elisa
    Ferrante, Daniela
    Meerpohl, Joerg J.
    Kartal, Mutlu
    Da Costa, Lydie
    Proust, Alexis
    Leblanc, Thierry
    Simansour, Maud
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Fröjmark, Anne-Sophie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Pospisilova, Dagmar
    Cmejla, Radek
    Beggs, Alan H.
    Sheen, Mee R.
    Landowski, Michael
    Buros, Christopher M.
    Clinton, Catherine M.
    Dobson, Lori J.
    Vlachos, Adrianna
    Atsidaftos, Eva
    Lipton, Jeffrey M.
    Ellis, Steven R.
    Ramenghi, Ugo
    Dianzani, Irma
    The ribosomal basis of Diamond-Blackfan Anemia: mutation and database update2010Ingår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 31, nr 12, s. 1269-1279Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Diamond-Blackfan Anemia (DBA) is characterized by a defect of erythroid progenitors and, clinically, by anemia and malformations. DBA exhibits an autosomal dominant pattern of inheritance with incomplete penetrance. Currently nine genes, all encoding ribosomal proteins (RP), have been found mutated in approximately 50% of patients. Experimental evidence supports the hypothesis that DBA is primarily the result of defective ribosome synthesis. By means of a large collaboration among six centers, we report here a mutation update that includes nine genes and 220 distinct mutations, 56 of which are new. The DBA Mutation Database now includes data from 355 patients. Of those where inheritance has been examined, 125 patients carry a de novo mutation and 72 an inherited mutation. Mutagenesis may be ascribed to slippage in 65.5% of indels, whereas CpG dinucleotides are involved in 23% of transitions. Using bioinformatic tools we show that gene conversion mechanism is not common in RP genes mutagenesis, notwithstanding the abundance of RP pseudogenes. Genotype-phenotype analysis reveals that malformations are more frequently associated with mutations in RPL5 and RPL11 than in the other genes. All currently reported DBA mutations together with their functional and clinical data are included in the DBA Mutation Database.

  • 27.
    Bremer, Anna
    et al.
    Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden..
    Giacobini, MaiBritt
    Nordenskjold, Magnus
    Brondum-Nielsen, Karen
    Mansouri, Mahmoud
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Anderlid, BrittMarie
    Schoumans, Jacqueline
    Screening for Copy Number Alterations in Loci Associated With Autism Spectrum Disorders by Two-Color Multiplex Ligation-Dependent Probe Amplification2010Ingår i: American journal of medical genetics. Part B, Neuropsychiatric genetics, ISSN 1552-4841, Vol. 153B, nr 1, s. 280-285Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The autism spectrum disorder (ASD) is a heterogenous condition characterized by impaired socialization and communication in association with stereotypic behaviors. ASD is highly heritable and heterogeneous with a complex genetic etiology. Recurrent submicroscopic deletions or duplications have been identified in a subgroup of individuals with ASD using array technology. Adequate genetic testing for these genomic imbalances have not yet been widely implemented in the diagnostic setting due to lack of feasible and cost-effective methods as well as difficulties to interpret the clinical significance of these small copy number variants (CNVs). We developed a multiplex ligation-dependent probe amplification (MLPA) assay to investigate its usefulness for detection of copy number alterations (CNAs) in autistic patients. This test proved to be easy to perform, fast, cost-effective, and suitable for reliable detection of multiple loci in a single reaction. We screened 148 autistic patients for 15 different loci covering 26 genes and found a 15q11-13 interstitial duplication that had escaped detection by conventional karyotyping in 1.3% of the patients. Synthetic probe MLPA allows for a flexible analysis of a continuously increasing number of CNAs associated with autism. Our result show that MLPA assay is an easy and cost-effective method for the identification of selected CNAs in diagnostic laboratories. (C) 2009 Wiley-Liss, Inc.

  • 28. Cario, Holger
    et al.
    Bode, H.
    Gustavsson, P.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Kohne, E.
    A microdeletion syndrome due to a 3-Mb deletion on 19q13.2--Diamond-Blackfan anemia associated with macrocephaly, hypotonia, and psychomotor retardation1999Ingår i: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 55, nr 6, s. 487-92Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We report on a boy with congenital pure red blood cell aplasia [Diamond Blackfan anemia (DBA)] and severe congenital hypotonia, macrocephaly, hypertelorism, a broad and tall forehead, medial epicanthus, and facial hypotonia with mouth-breathing and drooling, an affable and out-going personality, and a general psychomotor retardation. These features show similarity to the phenotype of the X-linked FG syndrome. DBA was diagnosed at the age of 4 months, and the boy underwent treatment with transfusion and with prednisolone. He had a normal 46, XY karyotype, but fluorescence in situ hybridization (FISH) analysis to metaphase chromosomes revealed a 3-Mb deletion on 19q13.2. This chromosomal region has previously been linked to the DBA phenotype and one 19q13 microdeletion has been identified in a patient with DBA. This deletion coincides with the deletion reported here. We suggest that the complex phenotype of our patient, including both DBA and the associated features, represent a microdeletion syndrome.

  • 29.
    Carling, Tobias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Szabo, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Bai, Mei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Ridefelt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Westin, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Gustavsson, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Trivedi, Sunita
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Brown, Edward M.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Rastad, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor2000Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 85, nr 5, s. 2042-7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Familial hyperparathyroidism (HPT), characterized by hypercalcemia and hypercalciuria, and familial benign hypocalciuric hypercalcemia (FHH) are the most common causes of hereditary hypercalcemia. The calcium-sensing receptor (CaR) regulates PTH secretion and renal calcium excretion. Heterozygous inactivating mutations of the gene cause FHH, whereas CaR gene mutations have not been demonstrated in HPT. In a kindred with 20 affected individuals, the hypercalcemic disorder segregated with inappropriately higher serum PTH and magnesium levels and urinary calcium levels than in unaffected members. Subtotal parathyroidectomy revealed parathyroid gland hyperplasia/adenoma and corrected the biochemical signs of the disorder in seven of nine individuals. Linkage analysis mapped the condition to markers flanking the CaR gene on chromosome 3q. Sequence analysis revealed a mutation changing phenylalanine to leucine at codon 881 of the CaR gene, representing the first identified point mutation located within the cytoplasmic tail of the CaR. A construct of the mutant receptor (F881L) was expressed in human embryonic kidney cells (HEK 293), and demonstrated a right-shifted dose-response relationship between the extracellular and intracellular calcium concentrations. The hypercalcemic disorder of the present family is caused by an inactivating point mutation in the cytoplasmic tail of the CaR and displays clinical characteristics atypical of FHH and primary HPT.

  • 30. Carlsson, G
    et al.
    van't Hooft, I
    Melin, M
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Entesarian, M
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Laurencikas, E
    Nennesmo, I
    Trebińska, A
    Grzybowska, E
    Palmblad, J
    Dahl, N
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Nordenskjöld, M
    Fadeel, B
    Henter, J-I
    Central nervous system involvement in severe congenital neutropenia: neurological and neuropsychological abnormalities associated with specific HAX1 mutations2008Ingår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 264, nr 4, s. 388-400Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVES: Homozygous mutations in the HAX1 gene were recently identified in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden. Our observations suggested that these patients also develop neurological and neuropsychological symptoms. METHODS: Detailed clinical studies and mutation analyses were performed in the surviving patients belonging to the Kostmann kindred and in two patients not related to this family, along with studies of HAX1 splice variant expression in normal human tissues. RESULTS: Five of six Kostmann family patients and one other patient from northern Sweden harboured homozygous HAX1 mutations (568C-->T, Q190X) and one carried a heterozygous ELA2 gene mutation. One Swedish patient of Kurdish extraction carried alternative homozygous HAX1 mutations (131G-->A, W44X). All the three patients with Q190X mutations who were alive and available for evaluation developed neurological disease with decreased cognitive function, and three of four patients who reached 10 years developed epilepsy. In contrast, the patients with the ELA2 and W44X HAX1 mutations, respectively, showed no obvious neurological abnormalities. Moreover, two alternative HAX1 splice variants were identified in normal human tissues, including the brain. Both transcripts contained exon 5, harbouring the Q190X mutation, whereas the 5' end of exon 2 containing the W44X mutation was spliced out from the second transcript. CONCLUSIONS: We describe neurological and neuropsychological abnormalities for the first time in Kostmann disease patients. These central nervous system symptoms appear to be associated with specific HAX1 mutations.

  • 31. Carlsson, Göran
    et al.
    Elinder, Göran
    Malmgren, Helena
    Trebinska, Alicja
    Grzybowska, Ewa
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Nordenskjöld, Magnus
    Fadeel, Bengt
    Compound heterozygous HAX1 mutations in a Swedish patient with severe congenital neutropenia and no neurodevelopmental abnormalities2009Ingår i: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 53, nr 6, s. 1143-1146Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Kostmann disease or severe congenital neutropenia (SCN) is an autosomal recessive disorder of neutrophil production. Homozygous HAX1 mutations were recently identified in SCN patients belonging to the original family in northern Sweden described by Kostmann. Moreover, recent studies have suggested an association between neurological dysfunction and HAX1 deficiency. Here we describe a patient with a compound heterozygous HAX1 mutation consisting of a nonsense mutation (c.568C > T, p.Glu190X) and a frame-shift mutation (c.91delG, p.Glu31LysfsX54) resulting in a premature stop codon. The patient has a history of neutropenia and a propensity for infections, but has shown no signs of neurodevelopmental abnormalities.

  • 32. Carlsson, Göran
    et al.
    Melin, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Ramme, Kim Göransdotter
    Nordenskjöld, Magnus
    Palmblad, Jan
    Henter, Jan-Inge
    Fadeel, Bengt
    Kostmann syndrome or infantile genetic agranulocytosis, part two: Understanding the underlying genetic defects in severe congenital neutropenia2007Ingår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 96, nr 6, s. 813-819Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Congenital neutropenia in man was first reported 50 years ago by the Swedish paediatrician Rolf Kostmann. He coined the term 'infantile genetic agranulocytosis' for this condition, which is now known as Kostmann syndrome. Recent studies have revealed mutations in ELA-2, encoding the neutrophil granule protease, neutrophil elastase, in autosomal dominant neutropenia, and mutations in HAX-1, encoding an anti-apoptotic protein, in autosomal recessive neutropenia.

    Conclusion: Future studies should aim to clarify the mechanisms underlying the evolution of secondary malignancies in these patients.

  • 33. Carlsson, Per-Inge
    et al.
    Borg, Erik
    Grip, Lars
    Dahl, Niklas
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Bondeson, Marie Louise
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Variability in noise susceptibility in a Swedish population: The role of 35delG mutation in the connexin 26 (GJB2) gene2004Ingår i: Audiological Medicine, ISSN 1651-386X, Vol. 1, nr 2, s. 123-130Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although it seems that genetic factors can influcence individual susceptiblity to noise, still very little is known about the genes or the mechanisms involved. The connexin 26 (cx26)(GJB2) gene is of particular interest to study in relation to noise, since the gene encodes a gap junction protein cx26. Noise has a metabolic and mechanical effect on the inner ear, and may therefore, interfere with gap junction channels. In order to investigate whether abnormally high susceptibility to noise induced hearing loss (NIHL) in humans is associated with the common 35delG mutation in the Cx26 gene, 1200 noise-exposed workers were investigated in Sweden. Using a selection procedure based on audiometric analysis, noise exposure data and questionnaires, noise-exposed workers were devided into two categories: noise susceptible and noise resistant. There was a correspondence in noise susceptibility between this noise-exposed population and the international reference ISO standard 1999. Blood samples were drawn from 245 highly selected male subjects (103 noise susceptible, 112 noise resistant and 30 randomized cases), and genomic DNA was analysed with respect to the Cx26 35delG mutation. The incidence of 35delG carriers among this cohort was determined by multiplex, allele-specific PCR. Two of the 245 subjects (0.8%-(95% confidence interval 0.1-2.9) were found to be heterozygous carriers of the 35delG mutation, while the remaining 243 individuals were all non-carriers. Both the heterozygous carriers were found in the noise susceptible group. Statistical evaluation of the results demonstrated no significant difference in carrier incidence between the noise susceptible and noise resistant individuals in our Swedish noise-exposed population. In conclusion, there was no support for a major role of Cx26 35delG mutation in explaining the variability in noise susceptibility in this Swedish population

  • 34. Chiocchetti, Annalisa
    et al.
    Gibello, Luisa
    Carando, Adriana
    Aspesi, Anna
    Secco, Paola
    Garelli, Emanuela
    Loreni, Fabrizio
    Angelini, Mara
    Biava, Alessandra
    Dahl, Niklas
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dianzani, Umberto
    Ramenghi, Ugo
    Santoro, Claudio
    Dianzani, Irma
    Interactions between RPS19, mutated in Diamond-Blackfan anemia, and the PIM-1 oncoprotein.2005Ingår i: Haematologica, ISSN 1592-8721, Vol. 90, nr 11, s. 1453-62Artikel i tidskrift (Refereegranskat)
  • 35. Cossee, Mireille
    et al.
    Durr, Alexandra
    Schmitt, Michèle
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Trouillas, Paul
    Allinson, Patricia
    Kostrzewa, Markus
    Nivelon-Chevallier, Annie
    Gustavson, Karl-Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Kohlschutter, Alfried
    Müller, Ulrich
    Mandel, Jean-Louis
    Brice, Alexis
    Koenig, Michel
    Cavalcanti, Francesca
    Tammaro, Angela
    De Michele, Giuseppe
    Filla, Alessandro
    Cocozza, Sergio
    Labuda, Malgorzata
    Montermini, Laura
    Poirier, Josée
    Pandolfo, Massimo
    Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes1999Ingår i: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 45, nr 2, s. 200-206Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Friedreich's ataxia is the most common inherited ataxia. Ninety-six percent of patients are homozygous for GAA trinucleotide repeat expansions in the first intron of the frataxin gene. The remaining cases are compound heterozygotes for a GAA expansion and a frataxin point mutation. We report here the identification of 10 novel frataxin point mutations, and the detection of a previously described mutation (G130V) in two additional families. Most truncating mutations were in exon 1. All missense mutations were in the last three exons coding for the mature frataxin protein. The clinical features of 25 patients with identified frataxin point mutations were compared with those of 196 patients homozygous for the GAA expansion. A similar phenotype resulted from truncating mutations and from missense mutations in the carboxy-terminal half of mature frataxin, suggesting that they cause a comparable loss of function. In contrast, the only two missense mutations located in the amino-terminal half of mature frataxin (D122Y and G130V) cause an atypical and milder clinical presentation (early-onset spastic gait with slow disease progression, absence of dysarthria, retained or brisk tendon reflexes, and mild or no cerebellar ataxia), suggesting that they only partially affect frataxin function. The incidence of optic disk pallor was higher in compound heterozygotes than in expansion homozygotes, which might correlate with a very low residual level of normal frataxin produced from the expanded allele.

  • 36. Cui, Chang-Yi
    et al.
    Klar, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Georgii-Heming, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fröjmark, Anne-Sophie
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Baig, Shahid M.
    Schlessinger, David
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Frizzled6 Deficiency Disrupts the Differentiation Process of Nail Development2013Ingår i: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 133, nr 8, s. 1990-1997Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Nails protect the soft tissue of the tips of digits. The molecular mechanism of nail (and claw) development is largely unknown, but we have recently identified a Wnt receptor gene, Frizzled6 (Fzd6), that is mutated in a human autosomal-recessive nail dysplasia. To investigate the action of Fzd6 in claw development at the molecular level, we compared gene expression profiles of digit tips of wild-type and Fzd6(-/-) mice, and showed that Fzd6 regulates the transcription of a striking number of epidermal differentiation related genes. Sixty-three genes encoding keratins (Krts), keratin-associated proteins, and transglutaminases (Tgms) and their substrates were significantly downregulated in the knockout mice. Among them, four hard Krts, Krt86, Krt81, Krt34, and Krt31; two epithelial Krts, Krt6a and Krt6b; and Tgm 1 were already known to be involved in nail abnormalities when dysregulated. Immunohistochemical studies revealed decreased expression of Krt86, Krt6b, and involucrin in the epidermal portion of the claw field in the knockout embryos. We further showed that Dkk4, a Wnt antagonist, was significantly downregulated in Fzd6(-/-) mice along with Wnt, Bmp, and Hh family genes; and Dkk4 transgenic mice showed a subtly but appreciably modified claw phenotype. Thus, Fzd6-mediated Wnt signaling likely regulates the overall differentiation process of nail/claw formation.

  • 37.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Medicinsk genetik.
    Segmentella DNA-variationer driver genomets evolution. Ger nya infallsvinklar till förståelse av sjukdom och hälsa: [Segmental DNA variations impel the genome evolution. New approaches to the understanding of disease and health]2010Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, nr 17, s. 1138-1139Artikel i tidskrift (Övrigt vetenskapligt)
  • 38.
    Dahl, Niklas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Grandell, U.
    Martinsson, T.
    Allen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Johansson, L.
    Stolpe, L.
    Gyllensten, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Hjelte, L.
    Kollberg, H.
    Strandvik, B.
    Frequency of four cystic fibrosis mutations in a Swedish population1993Ingår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 82, nr 6-7, s. 609-Artikel i tidskrift (Refereegranskat)
  • 39.
    Dahlqvist, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Klar, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Hausser, I
    Anton-Lamprecht, I
    Hellström-Pigg, Maritta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gedde-Dahl, Jr
    Gånemo, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Vahlquist, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Congenital ichthyosis: mutations in ichthyin are associated with specific structural abnormalities in the granular layer of epidermis2007Ingår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 44, nr 10, s. 615-620Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of skin disorders. Several mutant genes have been identified in ARCI, but the association between genotype and phenotype is poorly understood.

    Methods: To investigate genotype–phenotype correlations in ARCI, we selected 27 patients from 18 families with specific ultrastructural features of the epidermis. The characteristic findings using electron microscopy (EM) were abnormal lamellar bodies and elongated membranes in the stratum granulosum, classified as ARCI EM type III. DNA samples from a subset of affected individuals were screened for homozygous genomic regions, and a candidate gene region was identified on chromosome 5q33. The region coincides with the ichthyin gene, previously reported as mutated in ARCI.

    Results: Mutation screening of ichthyin revealed missense or splice-site mutations in affected members from 16 of 18 (89%) families with characteristics of ARCI EM type III. In a control group of 18 patients with ARCI without EM findings consistent with type III, we identified one patient homozygous for a missense mutation in ichthyin.

    Discussion: Our findings indicate a strong association between ultrastructural abnormalities in the granular layer of epidermis and ichthyin mutations. The results also suggest that EM provides a tool for specific diagnosis in a genetically homogenous subgroup of patients with ARCI.

  • 40.
    Dahlqvist, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Klar, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Tiwari, Neha
    Schuster, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Törmä, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Badhai, Jitendra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Pujol, Ramon
    van Steensel, Maurice A. M.
    Brinkhuizen, Tjinta
    Gijezen, Lieke
    Chaves, Antonio
    Tadini, Gianluca
    Vahlquist, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    A single-nucleotide deletion in the POMP 5' UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK genodermatosis2010Ingår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 86, nr 4, s. 596-603Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    KLICK syndrome is a rare autosomal-recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic papules, and ichthyosiform scaling. In order to establish the genetic cause of this disorder, we collected DNA samples from eight European probands. Using high-density genome-wide SNP analysis, we identified a 1.5 Mb homozygous candidate region on chromosome 13q. Sequence analysis of the ten annotated genes in the candidate region revealed homozygosity for a single-nucleotide deletion at position c.-95 in the proteasome maturation protein (POMP) gene, in all probands. The deletion is included in POMP transcript variants with long 5' untranslated regions (UTRs) and was associated with a marked increase of these transcript variants in keratinocytes from KLICK patients. POMP is a ubiquitously expressed protein and functions as a chaperone for proteasome maturation. Immunohistochemical analysis of skin biopsies from KLICK patients revealed an altered epidermal distribution of POMP, the proteasome subunit proteins alpha 7 and beta 5, and the ER stress marker CHOP. Our results suggest that KLICK syndrome is caused by a single-nucleotide deletion in the 5' UTR of POMP resulting in altered distribution of POMP in epidermis and a perturbed formation of the outermost layers of the skin. These findings imply that the proteasome has a prominent role in the terminal differentiation of human epidermis.

  • 41.
    Dahlqvist, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Orlén, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Matsson, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Lönnerholm, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Gustavson, Karl-Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Multiple epiphyseal dysplasia: A clinical and genetic study of 12 cases in a Swedish 6-generation family2009Ingår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 80, nr 6, s. 711-715Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Multiple epiphyseal dysplasia (MED) is a common genetically and clinically heterogeneous skeletal dysplasia characterized by early-onset osteoarthritis, mainly in the hip and knee, and mild-to-moderate short stature. Here we report on a 6-generation MED family with 17 affected members. METHOD: The clinical and radiographic data on the 12 affected members still living were scrutinized. A structured inquiry comprising state of health and MED-related symptoms since birth up to the present time and the osteoarthritis outcome (KOOS) questionnaire were sent to all living family members with MED. The 5 known gene loci for autosomal dominant MED were analyzed for linkage, using fluorescence-labeled microsatellite markers. Linkage was ascertained with markers close to the COL9A2 gene, which was analyzed for mutations by sequencing. RESULTS: We identified an exon 3 donor splice mutation in the COL9A2 gene in all affected family members. Clinical, radiographic, and questionnaire data from affected family members suggested that MED caused by COL9A2 mutations starts in early childhood with knee pain accompanied by delayed ossification of femoral epiphyses. The disease then either stabilizes during puberty or progresses with additional joints becoming affected; joint surgery might be necessary. The progression of the disease also affects muscles, with increasing atrophy, resulting in muscle fatigue and pain. Muscular atrophy has not been reported earlier in cases with COL9A2 mutations. INTERPRETATION: In a patient with clinically suspected or verified MED, it is important to perform DNA-based analysis to identify a possible disease-causing mutation. This information can be used to carry out genetic risk assessment of other family members and to achieve an early and correct diagnosis in the children.

  • 42.
    Dahlqvist, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Törmä, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi.
    Badhai, Jitendra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    siRNA silencing of proteasome maturation protein (POMP) activates the unfolded protein response and constitutes a model for KLICK genodermatosis2012Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 7, nr 1, s. e29471-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Keratosis linearis with ichthyosis congenita and keratoderma (KLICK) is an autosomal recessive skin disorder associated with a single-nucleotide deletion in the 5'untranslated region of the proteasome maturation protein (POMP) gene. The deletion causes a relative switch in transcription start sites for POMP, predicted to decrease levels of POMP protein in terminally differentiated keratinocytes. To investigate the pathophysiology behind KLICK we created an in vitro model of the disease using siRNA silencing of POMP in epidermal air-liquid cultures. Immunohistochemical analysis of the tissue constructs revealed aberrant staining of POMP, proteasome subunits and the skin differentiation marker filaggrin when compared to control tissue constructs. The staining patterns of POMP siRNA tissue constructs showed strong resemblance to those observed in skin biopsies from KLICK patients. Western blot analysis of lysates from the organotypic tissue constructs revealed an aberrant processing of profilaggrin to filaggrin in samples transfected with siRNA against POMP. Knock-down of POMP expression in regular cell cultures resulted in decreased amounts of proteasome subunits. Prolonged silencing of POMP in cultured cells induced C/EBP homologous protein (CHOP) expression consistent with an activation of the unfolded protein response and increased endoplasmic reticulum (ER) stress. The combined results indicate that KLICK is caused by reduced levels of POMP, leading to proteasome insufficiency in differentiating keratinocytes. Proteasome insufficiency disturbs terminal epidermal differentiation, presumably by increased ER stress, and leads to perturbed processing of profilaggrin. Our findings underline a critical role for the proteasome in human epidermal differentiation.

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  • 43.
    Dahlqvist, Johanna
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Westermark, Gunilla T.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Vahlquist, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ichthyin/NIPAL4 localizes to keratins and desmosomes in epidermis and Ichthyin mutations affect epidermal lipid metabolism2012Ingår i: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 304, nr 5, s. 377-386Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Autosomal recessive congenital ichthyosis (ARCI) is a group of disorders characterized by abnormal desquamation of the skin and a disrupted epidermal water barrier. Ichthyin/NIPAL4 gene mutations have been identified in a subgroup of ARCI patients, but the role of ichthyin in epidermis remains elusive. In order to obtain new insights concerning the characteristics of ichthyin and the ARCI pathogenesis, we studied the expression and localization of ichthyin and related epidermal components in cultured keratinocytes and skin sections from patients with Ichthyin mutations and healthy controls. We observed an up-regulation of Ichthyin mRNA levels after in vitro differentiation of keratinocytes from both a patient with Ichthyin mutations and controls. Confocal and electron microscopy analyses of immunolabeled skin sections revealed that ichthyin localizes to desmosomes and keratins in both patients with mutant Ichthyin and controls, with an increased immunolabeling in patients. Nile red lipid analysis of skin sections exposed intra-cellular lipid accumulations in cells of the granular and cornified layers in patients but not in controls, consistent with the pathognomonic lipid membrane structures previously identified in epidermis from patients. Our combined findings indicate that ichthyin is associated with keratins and desmosomes in epidermis and is involved in lipid metabolism, possibly through processing of lamellar bodies. These results provide new clues to the understanding of the epidermal water barrier and the pathogenesis in ARCI.

  • 44.
    Davis, Kasey N.
    et al.
    Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA.;Stanford Univ, Sch Med, Dept Genet, Palo Alto, CA 94304 USA..
    Qu, Ping-Ping
    Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA.;Stanford Univ, Sch Med, Dept Genet, Palo Alto, CA 94304 USA..
    Ma, Shining
    Stanford Univ, Dept Stat, Stanford, CA 94305 USA..
    Lin, Ling
    Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA.;Stanford Univ, Sch Med, Ctr Narcolepsy, Palo Alto, CA 94304 USA..
    Plastini, Melanie
    Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA.;Stanford Univ, Sch Med, Dept Genet, Palo Alto, CA 94304 USA..
    Dahl, Niklas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik och neurobiologi.
    Plazzi, Giuseppe
    IRCCS, Ist Sci Neurol Bologna, I-40139 Bologna, Italy.;Univ Modena & Reggio Emilia, Dept Biomed Metab & Neural Sci, I-41125 Modena, Italy..
    Pizza, Fabio
    IRCCS, Ist Sci Neurol Bologna, I-40139 Bologna, Italy.;Univ Bologna, Dept Biomed & Neuromotor Sci, I-40126 Bologna, Italy..
    O'Hara, Ruth
    Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA..
    Wong, Wing Hung
    Stanford Univ, Dept Stat, Stanford, CA 94305 USA.;Stanford Univ, Sch Med, Dept Biomed Data Sci, Palo Alto, CA 94304 USA..
    Hallmayer, Joachim
    Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA..
    Mignot, Emmanuel
    Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA.;Stanford Univ, Sch Med, Ctr Narcolepsy, Palo Alto, CA 94304 USA..
    Zhang, Xianglong
    Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA.;Stanford Univ, Sch Med, Dept Genet, Palo Alto, CA 94304 USA..
    Urban, Alexander E.
    Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA.;Stanford Univ, Sch Med, Dept Genet, Palo Alto, CA 94304 USA..
    Mutations in human DNA methyltransferase DNMT1 induce specific genome-wide epigenomic and transcriptomic changes in neurodevelopment2023Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 32, nr 21, s. 3105-3120Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    DNA methyltransferase type 1 (DNMT1) is a major enzyme involved in maintaining the methylation pattern after DNA replication. Mutations in DNMT1 have been associated with autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN). We used fibroblasts, induced pluripotent stem cells (iPSCs) and induced neurons (iNs) generated from patients with ADCA-DN and controls, to explore the epigenomic and transcriptomic effects of mutations in DNMT1. We show cell type–specific changes in gene expression and DNA methylation patterns. DNA methylation and gene expression changes were negatively correlated in iPSCs and iNs. In addition, we identified a group of genes associated with clinical phenotypes of ADCA-DN, including PDGFB and PRDM8 for cerebellar ataxia, psychosis and dementia and NR2F1 for deafness and optic atrophy. Furthermore, ZFP57, which is required to maintain gene imprinting through DNA methylation during early development, was hypomethylated in promoters and exhibited upregulated expression in patients with ADCA-DN in both iPSC and iNs. Our results provide insight into the functions of DNMT1 and the molecular changes associated with ADCA-DN, with potential implications for genes associated with related phenotypes.

  • 45.
    Delvallée, Clarisse
    et al.
    Laboratoire de Génétique Médicale, Institut de génétique médicale d'Alsace IGMA, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg UMRS_1112, Strasbourg, France.
    Nicaise, Samuel
    Laboratoire de Génétique Médicale, Institut de génétique médicale d'Alsace IGMA, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg UMRS_1112, Strasbourg, France.
    Antin, Manuela
    Laboratoires de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
    Leuvrey, Anne-Sophie
    Laboratoires de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
    Nourisson, Elsa
    Laboratoires de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
    Leitch, Carmen C
    Advanced Center for Translational and Genetic Medicine (ACT‐GeM), Stanley Manne Children's Research Institute, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
    Kellaris, Georgios
    Advanced Center for Translational and Genetic Medicine (ACT‐GeM), Stanley Manne Children's Research Institute, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
    Stoetzel, Corinne
    Laboratoire de Génétique Médicale, Institut de génétique médicale d'Alsace IGMA, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg UMRS_1112, Strasbourg, France.
    Geoffroy, Véronique
    Laboratoire de Génétique Médicale, Institut de génétique médicale d'Alsace IGMA, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg UMRS_1112, Strasbourg, France.
    Scheidecker, Sophie
    Laboratoire de Génétique Médicale, Institut de génétique médicale d'Alsace IGMA, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg UMRS_1112, Strasbourg, France; Laboratoires de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
    Keren, Boris
    Institut du Cerveau et de la Moelle épinière (ICM), Sorbonne Université, Paris, France; AP‐HP, Hôpital de la Pitié‐Salpêtrière, Département de Génétique, Paris, France.
    Depienne, Christel
    Institut du Cerveau et de la Moelle épinière (ICM), Sorbonne Université, Paris, France; Institute of Human Genetics, University Hospital Essen, University of Duisburg‐Essen, Essen, Germany.
    Klar, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnkirurgisk forskning.
    Dahl, Niklas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnkirurgisk forskning.
    Deleuze, Jean-François
    Centre National de Recherche en Génomique Humaine (CNRGH), Institut de biologie François Jacob, Evry, France.
    Génin, Emmanuelle
    Inserm UMR1078, CHRU Brest, Univ Brest, Brest, France.
    Redon, Richard
    Université de Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.
    Demurger, Florence
    Service de Génétique Médicale, Centre Hospitalier Bretagne Atlantique, Vannes, France.
    Devriendt, Koenraad
    Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium.
    Mathieu-Dramard, Michèle
    Centre d'activité de génétique clinique, CLAD nord de France, CHU Amiens, Amiens, France.
    Poitou-Bernert, Christine
    Assistance Publique Hôpitaux de Paris, Nutrition Department Pitié‐Salpêtrière Hospital; Sorbonne Université, INSERM, NutriOmics Research Unit, Paris, France.
    Odent, Sylvie
    Centre de Référence Maladies Rares CLAD‐Ouest, Service de Génétique Clinique, CHU Rennes, Rennes, France ; CNRS, IGDR (Institut de Génétique et Développement de Rennes) UMR 6290, Université de Rennes, Rennes, France.
    Katsanis, Nicholas
    Advanced Center for Translational and Genetic Medicine (ACT‐GeM), Stanley Manne Children's Research Institute, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
    Mandel, Jean-Louis
    Laboratoires de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U964, Université de Strasbourg, Dept Transl Med and Neurogenetics Illkirch, France.
    Davis, Erica E
    Advanced Center for Translational and Genetic Medicine (ACT‐GeM), Stanley Manne Children's Research Institute, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
    Dollfus, Hélène
    Laboratoire de Génétique Médicale, Institut de génétique médicale d'Alsace IGMA, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg UMRS_1112, Strasbourg, France ; Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France ; Filière SENSGENE, Centre de Référence pour les affections rares en génétique ophtalmologique, CARGO, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
    Muller, Jean
    Laboratoire de Génétique Médicale, Institut de génétique médicale d'Alsace IGMA, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg UMRS_1112, Strasbourg, France; Laboratoires de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
    A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome2021Ingår i: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 99, nr 2, s. 318-324Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment and renal failure. Pathogenic variants in 24 genes account for the molecular basis of >80% of cases. Toward saturated discovery of the mutational basis of the disorder, we carefully explored our cohorts and identified a hominid-specific SINE-R/VNTR/Alu type F (SVA-F) insertion in exon 13 of BBS1 in eight families. In six families, the repeat insertion was found in trans with c.1169 T > G, p.Met390Arg and in two families the insertion was found in addition to other recessive BBS loci. Whole genome sequencing, de novo assembly and SNP array analysis were performed to characterize the genomic event. This insertion is extremely rare in the general population (found in 8 alleles of 8 BBS cases but not in >10 800 control individuals from gnomAD-SV) and due to a founder effect. Its 2435 bp sequence contains hallmarks of LINE1 mediated retrotransposition. Functional studies with patient-derived cell lines confirmed that the BBS1 SVA-F is deleterious as evidenced by a significant depletion of both mRNA and protein levels. Such findings highlight the importance of dedicated bioinformatics pipelines to identify all types of variation.

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  • 46. Dianzani, Irma
    et al.
    Garelli, E.
    Gustavsson, P.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Carando, A.
    Gustafsson, B.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Annerén, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Rapp-Hodgkin and AEC syndromes due to a new frameshift mutation in the TP63 gene2003Ingår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 40, nr 12, s. e133-Artikel i tidskrift (Refereegranskat)
  • 47.
    Draptchinskaia, Natalia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gustavsson, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Andersson, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Pettersson, Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Willig, Thiébaut-Noël
    Dianzani, Irma
    Ball, Sarah
    Tchernia, Gil
    Klar, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Matsson, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Tentler, Dimitri
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Mohandas, Narla
    Carlsson, Birgit
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia1999Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 21, nr 2, s. 169-75Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Diamond-Blackfan anaemia (DBA) is a constitutional erythroblastopenia characterized by absent or decreased erythroid precursors. The disease, previously mapped to human chromosome 19q13, is frequently associated with a variety of malformations. To identify the gene involved in DBA, we cloned the chromosome 19q13 breakpoint in a patient with a reciprocal X;19 chromosome translocation. The breakpoint occurred in the gene encoding ribosomal protein S19. Furthermore, we identified mutations in RPS19 in 10 of 40 unrelated DBA patients, including nonsense, frameshift, splice site and missense mutations, as well as two intragenic deletions. These mutations are associated with clinical features that suggest a function for RPS19 in erythropoiesis and embryogenesis.

  • 48.
    Ebrahimi-Fakhari, Darius
    et al.
    Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA..
    Teinert, Julian
    Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;Univ Hosp Heidelberg, Ctr Paediat & Adolescent Med, Div Child Neurol & Metab Med, Heidelberg, Germany..
    Behne, Robert
    Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;Univ Hosp Wurzburg, Dept Neurol, Wurzburg, Germany..
    Wimmer, Miriam
    Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA..
    D'Amore, Angelica
    Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;IRCCS Fdn Stella Maris, Mol Med, Pisa, Italy..
    Eberhardt, Kathrin
    Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA..
    Brechmann, Barbara
    Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA..
    Ziegler, Marvin
    Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA..
    Jensen, Dana M.
    Univ Washington, Dept Pediat, Div Genet Med, Seattle, WA 98195 USA..
    Nagabhyrava, Premsai
    Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;Harvard Med Sch, Translat Neurosci Ctr, Boston Childrens Hosp, Boston, MA 02115 USA..
    Geisel, Gregory
    Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;Harvard Med Sch, Translat Neurosci Ctr, Boston Childrens Hosp, Boston, MA 02115 USA..
    Carmody, Erin
    Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;Harvard Med Sch, Translat Neurosci Ctr, Boston Childrens Hosp, Boston, MA 02115 USA..
    Shamshad, Uzma
    Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;Harvard Med Sch, Translat Neurosci Ctr, Boston Childrens Hosp, Boston, MA 02115 USA..
    Dies, Kira A.
    Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;Harvard Med Sch, Translat Neurosci Ctr, Boston Childrens Hosp, Boston, MA 02115 USA..
    Yuskaitis, Christopher J.
    Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA..
    Salussolia, Catherine L.
    Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA..
    Ebrahimi-Fakhari, Daniel
    Saarland Univ, Med Ctr, Pediat Neurol, Homburg, Germany.;Univ Childrens Hosp Muenster, Dept Gen Pediat, Munster, Germany..
    Pearson, Toni S.
    Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA..
    Saffari, Afshin
    Univ Hosp Heidelberg, Ctr Paediat & Adolescent Med, Div Child Neurol & Metab Med, Heidelberg, Germany..
    Ziegler, Andreas
    Univ Hosp Heidelberg, Ctr Paediat & Adolescent Med, Div Child Neurol & Metab Med, Heidelberg, Germany..
    Koelker, Stefan
    Univ Hosp Heidelberg, Ctr Paediat & Adolescent Med, Div Child Neurol & Metab Med, Heidelberg, Germany..
    Volkmann, Jens
    Univ Hosp Wurzburg, Dept Neurol, Wurzburg, Germany..
    Wiesener, Antje
    Friedrich Alexander Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany..
    Bearden, David R.
    Univ Rochester, Sch Med, Child Neurol, Rochester, NY USA..
    Lakhani, Shenela
    Weill Cornell Med Coll, Ctr Neurogenet, New York, NY USA..
    Segal, Devorah
    Weill Cornell Med Coll, Ctr Neurogenet, New York, NY USA.;Weill Cornell Med, Div Child Neurol, New York, NY USA..
    Udwadia-Hegde, Anaita
    Jaslok Hosp & Res Ctr, Dept Pediat Neurol, Mumbai, Maharashtra, India..
    Martinuzzi, Andrea
    IRCCS E Medea, Unita Operat Conegliano, Sci Inst, Treviso, Italy..
    Hirst, Jennifer
    Univ Cambridge, Cambridge Inst Med Res, Cambridge, England..
    Perlman, Seth
    Univ Iowa, Dept Pediat, Carver Coll Med, Div Neurol, Iowa City, IA 52242 USA..
    Takiyama, Yoshihisa
    Univ Yamanashi, Dept Neurol, Kofu, Yamanashi, Japan..
    Xiromerisiou, Georgia
    Papageorgiou Hosp, Dept Neurol, Thessaloniki, Greece..
    Vill, Katharina
    Ludwig Maximilians Univ Munchen, Dr von Hauner Childrens Hosp, Pediat Neurol & Dev Med, Munich, Germany..
    Walker, William O.
    Univ Washington, Sch Med, Dept Pediat, Seattle Childrens Hosp, Seattle, WA 98195 USA..
    Shukla, Anju
    Manipal Acad Higher Educ, Kasturba Med Coll, Dept Med Genet, Manipal, Karnataka, India..
    Gupta, Rachana Dubey
    Medanta Hosp, Pediat Neurol, Indore, Madhya Pradesh, India..
    Dahl, Niklas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnkirurgisk forskning.
    Aksoy, Ayse
    Dr Sami Ulus Hosp, Pediat Neurol, Ankara, Turkey..
    Verhelst, Helene
    Ghent Univ Hosp, Pediat Neurol, Ghent, Belgium..
    Delgado, Mauricio R.
    Univ Texas Southwestern Med Ctr Dallas, Dept Neurol, Dallas, TX USA..
    Pourova, Radka Kremlikova
    Charles Univ Prague, Med Fac 2, Dept Biol & Med Genet, Prague, Czech Republic.;UH Motol, Prague, Czech Republic..
    Sadek, Abdelrahim A.
    Sohag Univ, Fac Med, Pediat Neurol, Sohag, Egypt..
    Elkhateeb, Nour M.
    Cairo Univ, Pediat Neurol, Cairo, Egypt..
    Blumkin, Lubov
    Tel Aviv Univ, Wolfson Med Ctr, Sackler Sch Med, Pediat Neurol Unit,Movement Disorders Clin, Tel Aviv, Israel..
    Brea-Fernandez, Alejandro J.
    CIBERER, Grp Med Xenom, Santiago De Compostela, Spain..
    Dacruz-Alvarez, David
    Complexo Hosp Univ, Neurol Pediat, Santiago De Compostela, Spain..
    Smol, Thomas
    CHU Lille, RADEME, Inst Genet Med, Lille, France..
    Ghoumid, Jamal
    CHU Lille, RADEME, Inst Genet Med, Lille, France..
    Miguel, Diego
    Univ Fed Bahia, Serv Genet Med, Salvador, BA, Brazil..
    Heine, Constanze
    Univ Hosp Leipzig, Inst Human Genet, Leipzig, Germany..
    Schlump, Jan-Ulrich
    Evangel Krankenhaus, Pediat, Oberhausen, Germany..
    Langen, Hendrik
    Sozialpadiatr Zentrum Hannover, Hannover, Germany..
    Baets, Jonathan
    Univ Antwerp, Neurogenet Grp, Antwerp, Belgium.;Univ Antwerp, Neuromuscular Reference Ctr, Antwerp, Belgium.;Antwerp Univ Hosp, Antwerp, Belgium..
    Bulk, Saskia
    Ctr Hosp Univ Liege, Med Genet, Liege, Belgium..
    Darvish, Hossein
    Semnan Univ Med Sci, Canc Res Ctr, Semnan, Iran.;Semnan Univ Med Sci, Dept Med Genet, Semnan, Iran..
    Bakhtiari, Somayeh
    Phoenix Childrens Hosp, Barrow Neurol Inst, Phoenix, AZ USA..
    Kruer, Michael C.
    Phoenix Childrens Hosp, Barrow Neurol Inst, Phoenix, AZ USA..
    Lim-Melia, Elizabeth
    Maria Fareri Childrens Hosp, Pediat Med Genet, Valhalla, NY USA..
    Aydinli, Nur
    Acibadem Mehmet Ali Aydinlar Univ, Dept Pediat, Pediat Genet, Istanbul, Turkey..
    Alanay, Yasemin
    Istanbul Med Fac, Pediat Neurol, Istanbul, Turkey..
    El-Rashidy, Omnia
    Ain Shams Univ, Pediat, Cairo, Egypt..
    Nampoothiri, Sheela
    Amrita Inst Med Sci & Res Ctr, Cochin, Kerala, India..
    Patel, Chirag
    Royal Brisbane & Womens Hosp, Genet Hlth Queensland, Brisbane, Qld, Australia..
    Beetz, Christian
    Centogene AG, Rostock, Germany..
    Bauer, Peter
    Centogene AG, Rostock, Germany..
    Yoon, Grace
    Univ Toronto, Hosp Sick Children, Dept Paediat, Div Clin & Metab Genet, Toronto, ON, Canada..
    Guillot, Mireille
    Hosp Sick Children, Dept Paediat, Toronto, ON, Canada.;Univ Toronto, Toronto, ON, Canada..
    Miller, Steven P.
    Hosp Sick Children, Dept Paediat, Toronto, ON, Canada.;Univ Toronto, Toronto, ON, Canada..
    Bourinaris, Thomas
    UCL Inst Neurol, Dept Mol Neurosci, London, England..
    Houlden, Henry
    UCL Inst Neurol, Dept Mol Neurosci, London, England..
    Robelin, Laura
    Hop Univ Strasbourg, Serv Neurol, Strasbourg, France..
    Anheim, Mathieu
    Hop Univ Strasbourg, Serv Neurol, Strasbourg, France..
    Alamri, Abdullah S.
    Natl Neurosci Inst, King Fahad Med City, Pediat Neurol, Riyadh, Saudi Arabia..
    Mahmoud, Adel A. H.
    Imam Abdulrahman Bin Faisal Univ, Pediat, Dammam, Saudi Arabia..
    Inaloo, Soroor
    Shiraz Univ Med Sci, Neonatal Res Ctr, Shiraz, Iran..
    Habibzadeh, Parham
    Shiraz Univ Med Sci, Persian BayanGene Res & Training Ctr, Shiraz, Iran..
    Faghihi, Mohammad Ali
    Shiraz Univ Med Sci, Persian BayanGene Res & Training Ctr, Shiraz, Iran.;Univ Miami, Ctr Therapeut Innovat, Miami, FL USA.;Univ Miami, Dept Psychiat & Behav Sci, Miami, FL USA..
    Jansen, Anna C.
    UZ Brussel, Pediat Neurol Unit, Dept Pediat, Brussels, Belgium..
    Brock, Stefanie
    UZ Brussel, Pediat Neurol Unit, Dept Pediat, Brussels, Belgium..
    Roubertie, Agathe
    CHU Montpellier, Pediat Neurol, Montpellier, France..
    Darras, Basil T.
    Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA..
    Agrawal, Pankaj B.
    Harvard Med Sch, Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Newborn Med, Boston, MA 02115 USA.;Harvard Med Sch, Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Genet & Genom, Boston, MA 02115 USA..
    Santorelli, Filippo M.
    IRCCS Fdn Stella Maris, Mol Med, Pisa, Italy..
    Gleeson, Joseph
    Rady Childrens Hosp, Rady Childrens Inst Genom Med, San Diego, CA USA..
    Zaki, Maha S.
    Natl Res Ctr, Clin Genet Human Genet & Genome Res Div, Cairo, Egypt..
    Sheikh, Sarah, I
    Celgene, Translat Neurosci, Cambridge, MA USA..
    Bennett, James T.
    Univ Washington, Dept Pediat, Div Genet Med, Seattle, WA 98195 USA..
    Sahin, Mustafa
    Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA.;Harvard Med Sch, Translat Neurosci Ctr, Boston Childrens Hosp, Boston, MA 02115 USA..
    Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia2020Ingår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 143, nr 10, s. 2929-2944Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 +/- 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 +/- 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 +/- 5.1 years, SD) and later tetraplegia (mean age: 16.1 +/- 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 +/- 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 +/- 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.

  • 49.
    Eeg-Olofsson, Orvar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Kalimo, Hannu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Eeg-Olofsson, Karin Edebol
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Jagell, Sten
    Marklund, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Simonsson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Duchenne muscular dystrophy and idiopathic hyperCKemia in the same family2008Ingår i: European journal of paediatric neurology, ISSN 1090-3798, E-ISSN 1532-2130, Vol. 12, nr 5, s. 404-7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Familial hyperCKemia is a rare condition, and a combination with Duchenne muscular dystrophy (DMD) is extremely rare. A boy showed muscle weakness from the age of 10 months and presented typical signs of DMD at the age of 18 months. The diagnosis was supported by markedly elevated serum creatine kinase (CK) value as well as by neurophysiological and muscle biopsy findings at the age of 23 months. The diagnosis was confirmed by identification of a stop codon in exon 43 (p.2095Arg>X) of the dystrophin gene. Interestingly, the father and his near relatives had increased serum CK values without any clinical symptoms or signs, nor a defect in caveolin-3 gene. We suggest that the occurrence of familial hyperCKemia may have triggered the early onset of symptoms in our patient.

  • 50.
    Entesarian, Miriam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Carlsson, Birgit
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Mansouri, Mahmoud Reza
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Stattin, Eva-Lena
    Holmberg, Eva
    Golovleva, Irina
    Stefansson, Hreinn
    Klar, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    A chromosome 10 variant with a 12 Mb inversion [inv(10)(q11.22q21.1)] identical by descent in the Swedish population2009Ingår i: American Journal of Medical Genetics, ISSN 0148-7299, E-ISSN 1096-8628, Vol. 149A, nr 3, s. 380-386Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We identified a paracentric inversion of chromosome 10 [inv(10)(q11.22q21.1)] in 0.20% of Swedish individuals (15/7,439) referred for cytogenetic analysis. A retrospective analysis of 8,896 karyotypes from amniocenteses in Sweden revealed a carrier frequency of 0.079% (7/8,896) for the inversion. Cloning and detailed analysis of the inversion breakpoint regions show enrichment for interspersed repeat elements and AT-stretches. The centromeric breakpoint coincides with that of a predicted inversion from HapMap data, which suggests that this region is involved in several chromosome 10 variants. No known gene or predicted transcript are disrupted by the inversion which spans approximately 12 Mb. Carriers from four non-related Swedish families have identical inversion breakpoints and haplotype analysis confirmed that the rearrangement is identical by descent. Diagnosis was retrieved in 6 out of the 15 carriers referred for cytogenetic analysis. No consistent phenotype was found to be associated with the inversion. Our study demonstrates that the inv(10)(q11.22q21.1) is a rare and inherited chromosome variant with a broad geographical distribution in Sweden.

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