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  • 1. Becker, Kerstin
    et al.
    Di Donato, Nataliya
    Holder-Espinasse, Muriel
    Andrieux, Joris
    Cuisset, Jean-Marie
    Vallée, Louis
    Plessis, Ghislaine
    Jean, Nolwenn
    Delobel, Bruno
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ravn, Kirstine
    Tümer, Zeynep
    Tinschert, Sigrid
    Schrock, Evelin
    Jønch, Aia Elise
    Hackmann, Karl
    De novo microdeletions of chromosome 6q14.1-q14.3 and 6q12.1-q14.1 in two patients with intellectual disability: further delineation of the 6q14 microdeletion syndrome and review of the literature2012In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 55, no 8-9, p. 490-497Article in journal (Refereed)
    Abstract [en]

    Interstitial 6q deletions can cause a variable phenotype depending on the size and location of the deletion. 6q14 deletions have been associated with intellectual disability and a distinct pattern of minor anomalies, including upslanted palpebral fissures with epicanthal folds, a short nose with broad nasal tip, anteverted nares, long philtrum, and thin upper lip. In this study we describe two patients with overlapping 6q14 deletions presenting with developmental delay and characteristic dysmorphism. Molecular karyotyping using array CGH analysis revealed a de novo 8.9 Mb deletion at 6q14.1-q14.3 and a de novo 11.3 Mb deletion at 6q12.1-6q14.1, respectively. We provide a review of the clinical features of twelve other patients with 6q14 deletions detected by array CGH analysis. By assessing all reported data we could not identify a single common region of deletion. Possible candidate genes in 6q14 for intellectual disability might be FILIP1, MYO6, HTR1B, and SNX14.

  • 2. Bena, Frederique
    et al.
    Bruno, Damien L.
    Eriksson, Mats
    van Ravenswaaij-Arts, Conny
    Stark, Zornitza
    Dijkhuizen, Trijnie
    Gerkes, Erica
    Gimelli, Stefania
    Ganesamoorthy, Devika
    Thuresson, Ann Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Labalme, Audrey
    Till, Marianne
    Bilan, Frederic
    Pasquier, Laurent
    Kitzis, Alain
    Dubourgm, Christele
    Rossi, Massimiliano
    Bottani, Armand
    Gagnebin, Maryline
    Sanlaville, Damien
    Gilbert-Dussardier, Brigitte
    Guipponi, Michel
    van Haeringen, Arie
    Kriek, Marjolein
    Ruivenkamp, Claudia
    Antonarakis, Stylianos E.
    Anderlid, Britt Marie
    Slater, Howard R.
    Schoumans, Jacqueline
    Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature2013In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 162B, no 4, p. 388-403Article in journal (Refereed)
    Abstract [en]

    This study aimed to elucidate the observed variable phenotypic expressivity associated with NRXN1 (Neurexin 1) haploinsufficiency by analyses of the largest cohort of patients with NRXN1 exonic deletions described to date and by comprehensively reviewing all comparable copy number variants in all disease cohorts that have been published in the peer reviewed literature (30 separate papers in all). Assessment of the clinical details in 25 previously undescribed individuals with NRXN1 exonic deletions demonstrated recurrent phenotypic features consisting of moderate to severe intellectual disability (91%), severe language delay (81%), autism spectrum disorder (65%), seizures (43%), and hypotonia (38%). These showed considerable overlap with previously reported NRXN1-deletion associated phenotypes in terms of both spectrum and frequency. However, we did not find evidence for an association between deletions involving the -isoform of neurexin-1 and increased head size, as was recently published in four cases with a deletion involving the C-terminus of NRXN1. We identified additional rare copy number variants in 20% of cases. This study supports a pathogenic role for heterozygous exonic deletions of NRXN1 in neurodevelopmental disorders. The additional rare copy number variants identified may act as possible phenotypic modifiers as suggested in a recent digenic model of neurodevelopmental disorders. 

  • 3. Boudry-Labis, Elise
    et al.
    Demeer, Benedicte
    Le Caignec, Cedric
    Isidor, Bertrand
    Mathieu-Dramard, Michele
    Plessis, Ghislaine
    George, Alice M.
    Taylor, Juliet
    Aftimos, Salim
    Wiemer-Kruel, Adelheid
    Kohlhase, Juergen
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Firth, Helen
    Simonic, Ingrid
    Vermeesch, Joris
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Copin, Henri
    Love, Donald R.
    Andrieux, Joris
    A novel microdeletion syndrome at 9q21.13 characterised by mental retardation, speech delay, epilepsy and characteristic facial features2013In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 56, no 3, p. 163-170Article in journal (Refereed)
    Abstract [en]

    The increased use of array-CGH and SNP-arrays for genetic diagnosis has led to the identification of new microdeletion/microduplication syndromes and enabled genotype-phenotype correlations to be made. In this study, nine patients with 9q21 deletions were investigated and compared with four previously Decipher reported patients. Genotype-phenotype comparisons of 13 patients revealed several common major characteristics including significant developmental delay, epilepsy, neuro-behavioural disorders and recognizable facial features including hypertelorism, feature-less philtrum, and a thin upper lip. The molecular investigation identified deletions with different breakpoints and of variable lengths, but the 750 kb smallest overlapping deleted region includes four genes. Among these genes, RORB is a strong candidate for a neurological phenotype. To our knowledge, this is the first published report of 9q21 microdeletions and our observations strongly suggest that these deletions are responsible for a new genetic syndrome characterised by mental retardation with speech delay, epilepsy, autistic behaviour and moderate facial dysmorphy. 

  • 4.
    de Ståhl, Teresita Díaz
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sandgren, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Piotrowski, Arkadiusz
    Nord, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Andersson, Robin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Bogdan, Adam
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Poplawski, Andrzej
    von Tell, Desiree
    Hansson, Caisa M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Elshafie, Amir I.
    Elghazali, Gehad
    Imreh, Stephan
    Nordenskjöld, Magnus
    Upadhyaya, Meena
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
    Bruder, Carl E. G.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Profiling of copy number variations (CNVs) in healthy individuals from three ethnic groups using a human genome 32 K BAC-clone-based array2008In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 29, no 3, p. 398-408Article in journal (Refereed)
    Abstract [en]

    To further explore the extent of structural large-scale variation in the human genome, we assessed copy number variations (CNVs) in a series of 71 healthy subjects from three ethnic groups. CNVs were analyzed using comparative genomic hybridization (CGH) to a BAC array covering the human genome, using DNA extracted from peripheral blood, thus avoiding any culture-induced rearrangements. By applying a newly developed computational algorithm based on Hidden Markov modeling, we identified 1,078 autosomal CNVs, including at least two neighboring/overlapping BACs, which represent 315 distinct regions. The average size of the sequence polymorphisms was approximately 350 kb and involved in total approximately 117 Mb or approximately 3.5% of the genome. Gains were about four times more common than deletions, and segmental duplications (SDs) were overrepresented, especially in larger deletion variants. This strengthens the notion that SDs often define hotspots of chromosomal rearrangements. Over 60% of the identified autosomal rearrangements match previously reported CNVs, recognized with various platforms. However, results from chromosome X do not agree well with the previously annotated CNVs. Furthermore, data from single BACs deviating in copy number suggest that our above estimate of total variation is conservative. This report contributes to the establishment of the common baseline for CNV, which is an important resource in human genetics.

  • 5. Demeer, Benedicte
    et al.
    Andrieux, Joris
    Receveur, Aline
    Morin, Gilles
    Petit, Florence
    Julia, Sophie
    Plessis, Ghislaine
    Martin-Coignard, Dominique
    Delobel, Bruno
    Firth, Helen V.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Dosen, Sandrine Lanco
    Sjoers, Kerstin
    Le Caignec, Cedric
    Devriendt, Koenraad
    Mathieu-Dramard, Michele
    Duplication 16p13.3 and the CREBBP gene: Confirmation of the phenotype2013In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 56, no 1, p. 26-31Article in journal (Refereed)
    Abstract [en]

    The introduction of molecular karyotyping technologies into the diagnostic work-up of patients with congenital disorders permitted the identification and delineation of novel microdeletion and microduplication syndromes. Interstitial 16p13.3 duplication, encompassing the CREBBP gene, which is mutated or deleted in the Rubinstein-Taybi syndrome, have been proposed to cause a recognisable syndrome with variable intellectual disability, normal growth, mild facial dysmorphism, mild anomalies of the extremities, and occasional findings such as developmental defects of the heart, genitalia, palate or the eyes. We here report the phenotypic and genotypic delineation of 9 patients carrying a submicroscopic 16p13.3 duplication, including the smallest 16p13.3 duplication reported so far. Careful clinical assessment confirms the distinctive clinical phenotype and also defines frequent associated features : marked speech problems, frequent ocular region involvement with upslanting of the eyes, narrow palpebral fissures, ptosis and strabismus, frequent proximal implantation of thumbs, cleft palate/bifid uvula and inguinal hernia. It also confirms that CREBBP is the critical gene involved in the duplication 16p13.3 syndrome.

  • 6.
    Gullberg, Donald
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Tingström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Thuresson, A C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical and Physiological Chemistry.
    Olsson, L
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Zoology.
    Terracio, L
    Borg, T K
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Beta 1 integrin-mediated collagen gel contraction is stimulated by PDGF1990In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 186, no 2, p. 264-272Article in journal (Refereed)
  • 7.
    Halvardson, Jonatan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhao, Jin J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zaghlool, Ammar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wentzel, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Georgii-Hemming, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Karolinska Univ Hosp, Dept Mol Med & Surg, Stockholm, Sweden.
    Månsson, Else
    Orebro Univ Hosp, Dept Pediat, Orebro, Sweden.
    Ederth Sävmarker, Helena
    Gavle Cent Hosp, Dept Pediat, Gavle, Sweden.
    Brandberg, Göran
    Pediat Clin, Falun, Sweden.
    Soussi Zander, Cecilia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Feuk, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Mutations in HECW2 are associated with intellectual disability and epilepsy2016In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 53, no 10, p. 697-704Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: De novo mutations are a frequent cause of disorders related to brain development. We report the results of screening patients diagnosed with both epilepsy and intellectual disability (ID) using exome sequencing to identify known and new causative de novo mutations relevant to these conditions.

    METHODS: Exome sequencing was performed on 39 patient-parent trios to identify de novo mutations. Clinical significance of de novo mutations in genes was determined using the American College of Medical Genetics and Genomics standard guidelines for interpretation of coding variants. Variants in genes of unknown clinical significance were further analysed in the context of previous trio sequencing efforts in neurodevelopmental disorders.

    RESULTS: In 39 patient-parent trios we identified 29 de novo mutations in coding sequence. Analysis of de novo and inherited variants yielded a molecular diagnosis in 11 families (28.2%). In combination with previously published exome sequencing results in neurodevelopmental disorders, our analysis implicates HECW2 as a novel candidate gene in ID and epilepsy.

    CONCLUSIONS: Our results support the use of exome sequencing as a diagnostic approach for ID and epilepsy, and confirm previous results regarding the importance of de novo mutations in this patient group. The results also highlight the utility of network analysis and comparison to previous large-scale studies as strategies to prioritise candidate genes for further studies. This study adds knowledge to the increasingly growing list of causative and candidate genes in ID and epilepsy and highlights HECW2 as a new candidate gene for neurodevelopmental disorders.

  • 8.
    Isaksson, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stenberg, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Dahl, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Bondeson, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    MLGA--a rapid and cost-efficient assay for gene copy-number analysis2007In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 35, no 17, p. e115-Article in journal (Refereed)
    Abstract [en]

    Structural variation is an important cause of genetic variation. Whole genome analysis techniques can efficiently identify copy-number variable regions but there is a need for targeted methods, to verify and accurately size variable regions, and to diagnose large sample cohorts. We have developed a technique based on multiplex amplification of size-coded selectively circularized genomic fragments, which is robust, cheaper and more rapid than current multiplex targeted copy-number assays.

  • 9. Lynch, Sally Ann
    et al.
    Foulds, Nicola
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Collins, Amanda L.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Hedberg, Bernt-Oves
    Delaney, Carol A.
    Iremonger, James
    Murray, Caroline M.
    Crolla, John A.
    Costigan, Colm
    Lam, Wayne
    Fitzpatrick, David R.
    Regan, Regina
    Ennis, Sean
    Sharkey, Freddie
    The 12q14 microdeletion syndrome: six new cases confirming the role of HMGA2 in growth2011In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 19, no 5, p. 534-539Article in journal (Refereed)
    Abstract [en]

    We report six patients with array deletions encompassing 12q14. Out of a total of 2538 array investigations carried out on children with developmental delay and dysmorphism in three diagnostic testing centres, six positive cases yielded a frequency of 1 in 423 for this deletion syndrome. The deleted region in each of the six cases overlaps significantly with previously reported cases with microdeletions of this region. The chromosomal range of the deletions extends from 12q13.3q15. In the current study, we report overlapping deletions of variable extent and size but primarily comprising chromosomal bands 12q13.3q14.1. Four of the six deletions were confirmed as de novo events. Two cases had deletions that included HMGA2, and both children had significant short stature. Neither case had osteopoikilosis despite both being deleted for LEMD3. Four cases had deletions that ended proximal to HMGA2 and all of these had much better growth. Five cases had congenital heart defects, including two with atrial septal defects, one each with pulmonary stenosis, sub-aortic stenosis and a patent ductus. Four cases had moderate delay, two had severe developmental delay and a further two had a diagnosis of autism. All six cases had significant speech delay with subtle facial dysmorphism.

  • 10.
    Mansouri, Mahmoud R
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Thuresson, Ann-Charlotte
    Isaksson, Magnus
    Stenberg, Johan
    Betancur, Catalina
    Leboyer, Marion
    Råstam, Maria
    Gillberg, I. Carina
    Gillberg, Christopher
    Langford, Cordelia
    Array-based comparative genome hybridisation for detection of gene copy number variation in autism: Identification of novel lociManuscript (Other academic)
  • 11.
    Mantripragada, Kiran K
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Piotrowski, Arek
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Diaz De Ståhl, Teresita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Grigelionis, Gintautas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ferner, R
    Griffiths, Sian
    Bolund, Lars
    Mautner, Victor
    Nordling, M
    Legius, E
    Vetrie, D
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Messiaen, L
    Upadhyaya, M
    Bruder, C E G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Dumanski, Jan P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Identification of novel deletion breakpoints bordered by segmental duplications in the NF1 locus using high resolution array-CGH2006In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 43, no 1, p. 28-38Article in journal (Refereed)
    Abstract [en]

    Background: Segmental duplications flanking the neurofibromatosis type 1 ( NF1) genelocus on 17q11 mediate most gene deletions in NF1 patients. However, the large size of the gene and the complexity of the locus architecture pose difficulties in deletion analysis. We report theconstruction and application of the first NF1 locus specific microarray, covering 2.24 Mb of 17q11,using a non- redundant approach for array design. The average resolution of analysis for the array is similar to 12 kb per measurement point with an increased average resolution of 6.4 kb for the NF1gene. Methods: We performed a comprehensive array- CGH analysis of 161 NF1 derived samples and identified heterozygous deletions of various sizes in 39 cases. The typical deletion was identified in26 cases, whereas 13 samples showed atypical deletion profiles. Results: The size of the atypical deletions, contained within the segment covered by the array, ranged from 6 kb to 1.6 Mb and their breakpoints could be accurately determined. Moreover, 10 atypical deletions were observed to share a common breakpoint either on the proximal or distal end of thedeletion. The deletions identified by array- CGH were independently confirmed using multiplex ligation- dependent probe amplification. Bioinformatic analysis of the entire locus identified 33segmental duplications. Conclusions: We show that at least one of these segmental duplications, which borders the proximal breakpoint located within the NF1 intron 1 in five atypical deletions, might represent a novel hot spot for deletions. Our array constitutes a novel and reliable tool offering significantly improved diagnostics for this common disorder.

  • 12.
    Martinez, J
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Ren, Yan-Guo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Hellman, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Aström, J
    Amersham Pharmacia Biotech.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    A 54-kDa fragment of the Poly(A)-specific ribonuclease is an oligomeric, processive, and cap-interacting Poly(A)-specific 3' exonuclease.2000In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 275, no 31, p. 24222-24230Article in journal (Refereed)
    Abstract [en]

    We have previously identified a HeLa cell 3' exonuclease specific for degrading poly(A) tails ofmRNAs, Here we report on the purification and identification of a calf thymus 54-kDa polypeptide associated witha similar 3' exonuclease activity. The 54-kDa polypeptide was shown to be a fragment of the poly(A)-specificribonuclease 74-kDa polypeptide. The native molecular mass of the nuclease activity was estimated to be 180-220 kDa, Protein/protein cross-linking revealed an oligomeric structure, most likely consisting of three subunits.The purified nuclease activity released 5'-AMP as the reaction product and degraded poly(A) in a highlyprocessive fashion. The activity required monovalent cations and was dependent on divalent metal ions. TheRNA substrate requirement was investigated, and it was found that the nuclease was highly poly(A)-specific and that only 3' end-located poly(A) was degraded by the activity. RNA substrates capped with m(7)G(5')ppp(5')G were more efficiently degraded than noncapped RNA substrates. Addition of free m7G(5')ppp(5')G cap analogue inhibited poly(A) degradation in vitro, suggesting a functional link between the RNA 5' end cap structure andpoly(A) degradation at the 3' end of the RNA.

  • 13.
    Nordvarg, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kyriakopoulou, Christina B.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Larsson, Birgitta
    Rodriguez-Martinez, Heriberto
    Virtanen, Anders
    Functional significance of multiple poly(A) polymerases: Modulation of a carboxyl terminally located regulatory region by alternative mRNA processingArticle in journal (Refereed)
  • 14.
    Nyström, Anna-Maja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ekvall, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Strömberg, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Holmström, Gerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ophthalmology.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Bondeson, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    A severe form of Noonan syndrome and autosomal dominant café-au-lait spots: evidence for different genetic origins2009In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 98, no 4, p. 693-698Article in journal (Refereed)
    Abstract [en]

    Aim: The clinical overlap among Noonan syndrome (NS), cardio-facio-cutaneous (CFC), LEOPARD and Costello syndromes as well as Neurofibromatosis type 1 is extensive, which complicates the process of diagnosis. Further genotype–phenotype correlations are required to facilitate future diagnosis of these patients. Therefore, investigations of the genetic cause of a severe phenotype in a patient with NS and the presence of multiple café-au-lait spots (CAL) spots in the patient and four members of the family were performed. Methods: Mutation analyses of candidate genes, PTPN11, NF1, SPRED1 and SPRED2, associated with these syndromes, were conducted using DNA sequencing. Results: A previously identified de novo mutation, PTPN11 F285L and an inherited NF1 R1809C substitution in the index patient were found. However, neither PTPN11 F285L, NF1 R1809C, SPRED1 nor SPRED2 segregated with CAL spots in the family. The results indicate that the familial CAL spots trait in this family is caused by a mutation in another gene, distinct from previous genes associated with CAL spots in these syndromes. Conclusion: We suggest that the atypical severe symptoms in the index patient may be caused by an additive effect on the F285L mutation in PTPN11 by another mutation, for example the NF1 R1809C or alternatively, the not yet identified gene mutation associated with CAL spots in this family.

  • 15.
    Nyström, Anna-Maja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ekvall, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Bondeson, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Investigation of gene dosage imbalances in patients with Noonan syndrome using multiplex ligation-dependent probe amplification analysis2010In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 53, no 3, p. 117-121Article in journal (Refereed)
    Abstract [en]

    The RAS-MAPK syndromes are a group of clinically and genetically related disorders caused by dysregulation of the RAS-MAPK pathway. A member of this group of disorders, Noonan syndrome (NS), is associated with several different genes within the RAS-MAPK pathway. To date, mutations in PTPN11, SOS1, KRAS, RAF1 and SHOC2 are known to cause NS and a small group of patients harbour mutations in BRAF, MEK1 or NRAS. The majority of the mutations are predicted to cause an up-regulation of the pathway; hence they are gain-of-function mutations. Despite recent advances in gene identification in NS, the genetic aetiology is still unknown in about of patients.To investigate the contribution of gene dosage imbalances of RAS-MAPK-related genes to the pathogenesis of NS, a multiplex ligation-dependent probe amplification (MLPA) assaywas developed. Two probe sets were designed for seven RAS-MAPK-syndrome-related candidate genes: PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1 and MEK2. The probe sets were validated in 15 healthy control individuals and in glioma tumour cell lines. Subsequently, 44 NS patients negative for mutations in known NS-associated genes were screened using the two probe sets. The MLPA results for the patients revealed no gene dosage imbalances. In conclusion, the present results exclude copy number variation of PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1 and MEK2 as a common pathogenic mechanism of NS. The validated and optimised RAS-MAPK probe sets presented here enable rapid high throughput screening of further patients with RAS-MAPK syndromes.

  • 16. Palomares, Maria
    et al.
    Delicado, Alicia
    Mansilla, Elena
    Luisa de Torres, Maria
    Vallespin, Elena
    Fernandez, Luis
    Martinez-Glez, Victor
    Garcia-Minaur, Sixto
    Nevado, Julian
    Santos Simarro, Fernando
    Ruiz-Perez, Victor L.
    Lynch, Sally Ann
    Sharkey, Freddie H.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Belligni, Elga F.
    Luisa Martinez-Fernandez, Maria
    Bermejo, Eva
    Nowakowska, Beata
    Kutkowska-Kazmierczak, Anna
    Bocian, Ewa
    Obersztyn, Ewa
    Luisa Martinez-Frias, Maria
    Hennekam, Raoul C. M.
    Lapunzina, Pablo
    Characterization of a 8q21.11 Microdeletion Syndrome Associated with Intellectual Disability and a Recognizable Phenotype2011In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 89, no 2, p. 295-301Article in journal (Refereed)
    Abstract [en]

    We report eight unrelated individuals with intellectual disability and overlapping submicroscopic deletions of 8q21.11 (0.66-13.55 Mb in size). The deletion was familial in one and simplex in seven individuals. The phenotype was remarkably similar and consisted of a round face with full cheeks, a high forehead, ptosis, cornea opacities, an underdeveloped alae, a short philtrum, a cupid's bow of the upper lip, down-turned corners of the mouth, micrognathia, low-set and prominent ears, and mild finger and toe anomalies (camptodactyly, syndactyly, and broadening of the first rays). Intellectual disability, hypotonia, decreased balance, sensorineural hearing loss, and unusual behavior were frequently observed. A high-resolution oligonucleotide array showed different proximal and distal breakpoints in all of the individuals. Sequencing studies in three of the individuals revealed that proximal and distal breakpoints were located in unique sequences with no apparent homology. The smallest region of overlap was a 539.7 kb interval encompassing three genes: a Zinc Finger Homeobox 4 (ZFHX4), one microRNA of unknown function, and one nonfunctional pseudogen. ZFHX4 encodes a transcription factor expressed in the adult human brain, skeletal muscle, and liver. It has been suggested as a candidate gene for congenital bilateral isolated ptosis. Our results suggest that the 8q21.11 submicroscopic deletion represents a clinically recognizable entity and that a haploinsufficient gene or genes within the minimal deletion region could underlie this syndrome.

  • 17. Popovici, Cornel
    et al.
    Busa, Tiffany
    Boute, Odile
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Perret, Odile
    Sigaudy, Sabine
    Soedergren, Tommy
    Andrieux, Joris
    Moncla, Anne
    Philip, Nicole
    Whole ARX Gene Duplication is Compatible With Normal Intellectual Development2014In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 164A, no 9, p. 2324-2327Article in journal (Refereed)
    Abstract [en]

    We report here on four males from three families carrying de novo or inherited small Xp22.13 duplications including the ARX gene detected by chromosomal microarray analysis (CMA). Two of these males had normal intelligence. Our report suggests that, unlike other XLMR genes like MECP2 and FMR1, the presence of an extra copy of the ARX gene may not be sufficient to perturb its developmental functions. ARX duplication does not inevitably have detrimental effects on brain development, in contrast with the effects of ARX haploinsufficiency. The abnormal phenotype ascribed to the presence of an extra copy in some male patients may have resulted from the effect of another, not yet identified, chromosomal or molecular anomaly, alone or in association with ARX duplication.

  • 18. Schoumans, Jacqueline
    et al.
    Wincent, Josephine
    Barbaro, Michela
    Djureinovic, Tatjana
    Maguire, Paula
    Forsberg, Lena
    Staaf, Johan
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Borg, Åke
    Nordgren, Ann
    Malm, Gunilla
    Anderlid, Britt Marie
    Comprehensive mutational analysis of a cohort of Swedish Cornelia de Lange syndrome patients2007In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 15, no 2, p. 143-149Article in journal (Refereed)
    Abstract [en]

    Cornelia de Lange syndrome (CdLS; OMIM 122470) is a rare multiple congenital anomaly/mental retardation syndrome characterized by distinctive dysmorphic facial features, severe growth and developmental delay and abnormalities of the upper limbs. About 50% of CdLS patients have been found to have heterozygous mutations in the NIPBL gene and a few cases were recently found to be caused by mutations in the X-linked SMC1L1 gene. We performed a mutation screening of all NIPBL coding exons by direct sequencing in 11 patients (nine sporadic and two familial cases) diagnosed with CdLS in Sweden and detected mutations in seven of the cases. All were de novo, and six of the mutations have not been previously described. Four patients without identifiable NIPBL mutations were subsequently subjected to multiplex ligation-dependent probe amplification analysis to exclude whole exon deletions/duplications of NIPBL. In addition, mutation analysis of the 5' untranslated region (5' UTR) of NIPBL was performed. Tiling resolution array comparative genomic hybridization analysis was carried out on these four patients to detect cryptic chromosome imbalances and in addition the boys were screened for SMC1L1 mutations. We found a de novo 9p duplication with a size of 0.6 Mb in one of the patients with a CdLS-like phenotype but no mutations were detected in SMC1L1. So far, two genes (NIPBL and SMC1L1) have been identified causing CdLS or CdLS-like phenotypes. However, in a considerable proportion of individuals demonstrating the CdLS phenotype, mutations in any of these two genes are not found and other potential loci harboring additional CdLS-causing genes should be considered.

  • 19.
    Schuster, Jens
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sundblom, Jimmy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hassin-Baer, Sharon
    Klopstock, Thomas
    Dichgans, Martin
    Cohen, Oren S.
    Raininko, Raili
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Melberg, Atle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms2011In: Neurogenetics, ISSN 1364-6745, E-ISSN 1364-6753, Vol. 12, no 1, p. 65-72Article in journal (Refereed)
    Abstract [en]

    Adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms features micturition urgency, constipation, erectile dysfunction, and orthostatic hypotension, usually followed by pyramidal signs and ataxia. Peripheral nerve conduction is normal. The disease is often mistaken for multiple sclerosis in the initial phase. There is a characteristic pattern of white matter changes in the brain and spinal cord on magnetic resonance imaging (MRI), mild atrophy of the brain, and a more marked atrophy of the spinal cord. ADLD is associated with duplications of the lamin B1 (LMNB1) gene but the mechanism by which the rearrangement conveys the phenotype is not fully defined. We analyzed four unrelated families segregating ADLD with autonomic symptoms for duplications of the LMNB1 gene. A single nucleotide polymorphism (SNP) array analysis revealed novel duplications spanning the entire LMNB1 gene in probands from each of the four families. We then analyzed the expression of lamin B1 in peripheral leukocytes by Western blot analysis in five patients from two available families. The protein levels of lamin B1 were found significantly increased. These results indicate that the ADLD phenotype associated with LMNB1 duplications is mediated by increased levels of the lamin B1 protein. Furthermore, we show that a molecular diagnosis for ADLD with autonomic symptoms can be obtained by a direct analysis of lamin B1 in peripheral leukocytes.

  • 20. Sharkey, Freddie H.
    et al.
    Foulds, N.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Collins, A. L.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Hedberg, B. O.
    Delaney, C. A.
    Iremonger, J.
    Murray, C. M.
    Maher, E.
    Crolla, J. A.
    Costigan, C.
    Lam, W.
    FitzPatrick, D.
    Regan, R.
    Ennis, S.
    Lynch, S. A.
    The 12q14 microdeletion syndrome, 6 new cases confirming the role of HMGA2 in growth2010In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 47, no Suppl. 1, p. S90-S90Article in journal (Other academic)
  • 21. Thierry, Gaelle
    et al.
    Beneteau, Claire
    Pichon, Olivier
    Flori, Elisabeth
    Isidor, Bertrand
    Popelard, Francoise
    Delrue, Marie-Ange
    Duboscq-Bidot, Laetitia
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    van Bon, Bregje W. M.
    Cailley, Dorothee
    Rooryck, Caroline
    Paubel, Agathe
    Metay, Corinne
    Dusser, Anne
    Pasquier, Laurent
    Beri, Mylene
    Bonnet, Celine
    Jaillard, Sylvie
    Dubourg, Christele
    Tou, Bassim
    Quere, Marie-Pierre
    Soussi Zander, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Toutain, Annick
    Lacombe, Didier
    Arveiler, Benoit
    de Vries, Bert B. A.
    Jonveaux, Philippe
    David, Albert
    Le Caignec, Cedric
    Molecular characterization of 1q44 microdeletion in 11 patients reveals three candidate genes for intellectual disability and seizures2012In: American Journal of Medical Genetics. Part A, ISSN 1552-4825, E-ISSN 1552-4833, Vol. 158A, no 7, p. 1633-1640Article in journal (Refereed)
    Abstract [en]

    Patients with a submicroscopic deletion at 1q43q44 present with intellectual disability (ID), microcephaly, craniofacial anomalies, seizures, limb anomalies, and corpus callosum abnormalities. However, the precise relationship between most of deleted genes and the clinical features in these patients still remains unclear. We studied 11 unrelated patients with 1q44 microdeletion. We showed that the deletions occurred de novo in all patients for whom both parents' DNA was available (10/11). All patients presented with moderate to severe ID, seizures and non-specific craniofacial anomalies. By oligoarray-based comparative genomic hybridization (aCGH) covering the 1q44 region at a high resolution, we obtained a critical deleted region containing two coding genesHNRNPU and FAM36Aand one non-coding geneNCRNA00201. All three genes were expressed in different normal human tissues, including in human brain, with highest expression levels in the cerebellum. Mutational screening of the HNRNPU and FAM36A genes in 191 patients with unexplained isolated ID did not reveal any deleterious mutations while the NCRNA00201 non-coding gene was not analyzed. Nine of the 11 patients did not present with microcephaly or corpus callosum abnormalities and carried a small deletion containing HNRNPU, FAM36A, and NCRNA00201 but not AKT3 and ZNF238, two centromeric genes. These results suggest that HNRNPU, FAM36A, and NCRNA00201 are not major genes for microcephaly and corpus callosum abnormalities but are good candidates for ID and seizures. 

  • 22.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Regulation of Mammalian Poly(A) Polymerase Activity2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Poly(A) polymerase (PAP) is the enzyme catalyzing the synthesis of the adenine tail to the 3’-end of mRNA. This A-tail is present on the majority of the primary RNA transcripts of protein-coding genes, and is important for mRNA stability, export to the cytoplasm and translation. Therefore, PAP is a key regulator of eukaryotic gene expression. This thesis describes the heterogeneity of PAP and the functional significance of multiple isoforms of PAP.

    PAP exists in many different isoforms generated by three different mechanisms, gene duplication, alternative mRNA processing and post-translational modification. In HeLa cell extracts three different forms of PAP being 90, 100 and 106 kDa in size have been detected, where the 106 kDa isoform is a phosphorylated version of the 100 kDa species. It is shown that the N-terminal region of PAP contains a region required for catalysis, while the C-terminal end is important for the interaction with the cleavage and polyadenylation specificity factor (CPSF). Interestingly, it was found that also the extreme N-terminal end is important for the interaction with CPSF. This region is post-translationally modified by phosphorylation. Five alternatively spliced forms of PAP mRNAs are encoded by the PAPOLA gene while one unique species is encoded by the PAPOLG gene. The analysis showed that the exact structure of the alternatively spliced C-terminal end of PAP played an important role for catalytic efficiency. Thus, the C-terminal end contains a region important for modulating the catalytic efficiency of PAP.

    Aminoglycoside antibiotics inhibit PAP activity, most likely by displacement of catalytically important divalent metal ions. Data shows that different aminoglycosides inhibit PAP activity by different mechanisms suggesting that the binding sites for the different aminoglycosides do not completely overlap. It is concluded that aminoglycosides interfere with enzymes important for housekeeping functions in mammalian cell, which may explain some of the toxic side effects caused by aminoglycoside antibiotics in clinical practice.

  • 23.
    Thuresson, Ann-Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Aström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Aström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Grönvik, Kjell Olov
    The National Veterinary Institute, Section of Immunology and Cell Culture, Biomedical Center, Uppsala.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
    Multiple forms of poly(A) polymerases in human cells1994In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 91, no 3, p. 979-983Article in journal (Refereed)
    Abstract [en]

    We have cloned human poly(A) polymerase (PAP) mRNA as cDNA in Escherichia coli. The primary structure of the mRNA was determined and compared to the bovine PAP mRNA sequence. The two sequences were 97% identical at the nucleotide level, which translated into 99% similarity at the amino acid level. Polypeptides representing recombinant PAP were expressed in E. coli, purified, and used as antigens to generate monoclonal antibodies. Western blot analysis using these monoclonal antibodies as probes revealed three PAPs, having estimated molecular masses of 90, 100, and 106 kDa in HeLa cell extracts. Fractionation of HeLa cells showed that the 90-kDa polypeptide was nuclear while the 100- and 106-kDa species were present in both nuclear and cytoplasmic fractions. The 106-kDa PAP was most likely a phosphorylated derivative of the 100-kDa species. PAP activity was recovered in vitro by using purified recombinant human PAP. Subsequent mutational analysis revealed that both the N- and C-terminal regions of PAP were important for activity and suggested that cleavage and polyadenylylation specificity factor (CPSF) interacted with the C-terminal region of PAP. Interestingly, tentative phosphorylation sites have been identified in this region, suggesting that phosphorylation/dephosphorylation may regulate the interaction between the two polyadenylylation factors PAP and CPSF.

  • 24.
    Thuresson, Ann-Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Bondeson, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Edeby, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ellis, P.
    Langford, C.
    Dumanski, Jan P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Whole-genome array-CGH for detection of submicroscopic chromosomal imbalances in children with mental retardation2007In: Cytogenetic and Genome Research, ISSN 1424-8581, E-ISSN 1424-859X, Vol. 118, no 1, p. 1-7Article in journal (Refereed)
    Abstract [en]

    Chromosomal imbalances are the major cause of mental retardation (MR). Many of these imbalances are caused by submicroscopic deletions or duplications not detected by conventional cytogenetic methods. Microarray-based comparative genomic hybridization (array-CGH) is considered to be superior for the investigation of chromosomal aberrations in children with MR, and has been demonstrated to improve the diagnostic detection rate of these small chromosomal abnormalities. In this study we used 1 Mb genome-wide array-CGH to screen 48 children with MR and congenital malformations for submicroscopic chromosomal imbalances, where the underlying cause was unknown. All children were clinically investigated and subtelomere FISH analysis had been performed in all cases. Suspected microdeletion syndromes such as deletion 22q11.2, Williams-Beuren and Angelman syndromes were excluded before array-CGH analysis was performed. We identified de novo interstitial chromosomal imbalances in two patients (4%), and an interstitial deletion inherited from an affected mother in one patient (2%). In another two of the children (4%), suspected imbalances were detected but were also found in one of the non-affected parents. The yield of identified de novo alterations detected in this study is somewhat less than previously described, and might reflect the importance of which selection criterion of patients to be used before array-CGH analysis is performed. However, array-CGH proved to be a high-quality and reliable tool for genome-wide screening of MR patients of unknown etiology.

  • 25.
    Thuresson, Ann-Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Kirsebom, Leif A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Virtanen, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Inhibition of poly(A) polymerase by aminoglycosides2007In: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 89, no 10, p. 1221-1227Article in journal (Refereed)
    Abstract [en]

    Aminoglycosides are potent inhibitors of bacterial growth and are used clinically as antibiotics. However, their usage has declined in recent years due to the emergence of resistance and severe toxic side effects. Here we show that human poly(A) polymerase gamma (PAPgamma) is inhibited by aminoglycosides. The inhibition was pH dependent and could be released by Mg(II) ions in a competitive manner suggesting that electrostatic interactions are important for inhibition and that the binding sites for aminoglycosides overlap with Mg(II) ion binding sites. Kinetic analysis revealed that aminoglycosides of the neomycin and kanamycin families behaved as mixed non-competitive inhibitors for the PAPgamma substrates oligoA15 and ATP. Interestingly, sisomicin and 5-epi-sisomycin showed a competitive mechanism of inhibition for the oligoA15 whereas they inhibited the ATP substrate mixed non-competitive. This implies that different aminoglycosides bind in different ways to a common binding pocket and suggests that the binding sites for related aminoglycosides are not overlapping even if they may share molecular determinants. Our study emphasizes the possibility that aminoglycoside toxicity could be due to interference with housekeeping enzymes involved in breaking and forming phosphodiester bonds.

  • 26.
    Thuresson, Ann-Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Van Buggenhout, Griet
    Sheth, Frenny
    Kamate, Mahesh
    Andrieux, Joris
    Clayton Smith, Jill
    Zander, Cecilia Soussi
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Whole-gene duplication of SCN2A and SCN3A is associated with neonatal seizures and a normal intellectual development2017In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 91, no 1, p. 106-110Article in journal (Refereed)
    Abstract [en]

    Duplications at 2q24.3 encompassing the voltage-gated sodium channel gene cluster are associated with early onset epilepsy. All cases described in the literature have presented in addition with different degrees of intellectual disability, and have involved neighbouring genes in addition to the sodium channel gene cluster. Here we report eight new cases with overlapping duplications at 2q24 ranging from 0.05 Mb to 7.63 Mb in size. Taken together with the previously reported cases, our study suggests that having an extra copy of SCN2A has an effect on epilepsy pathogenesis, causing benign familial infantile seizures which eventually disappear at the age of one to two years.. However, the number of copies of SCN2A does not appear to have an effect on cognitive outcome.

  • 27. Wang, Peter
    et al.
    Carrion, Prescilla
    Qiao, Ying
    Tyson, Christine
    Hrynchak, Monica
    Calli, Kristina
    Lopez-Rangel, Elena
    Andrieux, Joris
    Delobel, Bruno
    Duban-Bedu, Benedicte
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Liu, Xudong
    Rajcan-Separovic, Evica
    Lewis, M. E. Suzanne
    Genotype-phenotype analysis of 18q12.1-q12.2 copy number variation in autism2013In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 56, no 8, p. 420-425Article in journal (Refereed)
    Abstract [en]

    Autism Spectrum Disorders (ASD) are complex neurodevelopmental conditions characterized by delays in social interactions and communication as well as displays of restrictive/repetitive interests. DNA copy number variants have been identified as a genomic susceptibility factor in ASDs and imply significant genetic heterogeneity. We report a 7-year-old female with ADOS-G and ADI-R confirmed autistic disorder harbouring a de novo 4 Mb duplication (18q12.1). Our subject displays severely deficient expressive language, stereotypic and repetitive behaviours, mild intellectual disability (ID), focal epilepsy, short stature and absence of significant dysmorphic features. Search of the PubMed literature and DECIPHER database identified 4 additional cases involving 18q12.1 associated with autism and/or ID that overlap our case: one duplication, two deletions and one balanced translocation. Notably, autism and ID are seen with genomic gain or loss at 18q12.1, plus epilepsy and short stature in duplication cases, and hypotonia and tall stature in deletion cases. No consistent dysmorphic features were noted amongst the reviewed cases. We review prospective ASD/ID candidate genes integral to 18q12.1, including those coding for the desmocollin/desmoglein cluster, ring finger proteins 125 and 138, trafficking protein particle complex 8 and dystrobrevin-alpha. The collective clinical and molecular features common to microduplication 18q12.1 suggest that dosage-sensitive, position or contiguous gene effects may be associated in the etiopathogenesis of this autism-ID-epilepsy syndrome. 

  • 28.
    Wentzel, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    A maternal de novo non-reciprocal translocation results in a 6q13-q16 deletion in one offspring and a 6q13-q16 duplication in another2014In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 57, no 6, p. 259-263Article in journal (Refereed)
    Abstract [en]

    Here we report a case of two siblings with reciprocal aberrations, one presenting with a deletion and the other carrying two novel duplications at 6q13q16.1. Interestingly, both alterations were inherited from a healthy mother carrying a non-reciprocal translocation of 6q13q16 to 15q11. Deletions at 6q13q16.1 have been previously described; however this is the first characterisation of a 6q13q16.1 duplication. In this report we provide a comprehensive molecular and phenotypical characterisation of the affected siblings and discuss the profiles of previously identified patients carrying 6q deletions. (C) 2014 Elsevier Masson SAS. All rights reserved.

  • 29.
    Wentzel, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Unbalanced de novo translocation in mother resulting in one child with a 6q13-q16 deletion and one child with a 6q13-q16 duplicationManuscript (preprint) (Other academic)
    Abstract [en]

    Here we report on two sisters with reciprocal CNVs at 6q13-q16.1. Both the deletion and the duplication were inherited from the healthy mother carrying an insertion of 6q13-q16 to 15q11. The deleted region in one of the sisters has previously been described. However, to our knowledge this is the first report of a duplication at the region 6q13q16. In the report we submit a detailed phenotypical description of both patients as well as candidate genes for some of the various symptoms that the patients presented.

  • 30.
    Wentzel, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Fernström, Maria
    Öhrner, Ylva
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Clinical variability of the 22q11.2 duplication syndrome2008In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 51, no 6, p. 501-510Article in journal (Refereed)
    Abstract [en]

    The 22q11.2 duplication syndrome is an extremely variable disorder with a phenotype ranging from normal to learning disability and congenital defects. Both patients with a de novo 22q11.2 duplication and patients in whom the duplication has been inherited from a phenotypically normal parent have been reported. In this study we present two familial cases with a 3Mb 22q11.2 duplication detected by array-CGH. We also review the findings in 36 reported cases with the aim of delineating the phenotype of the 22q11.2 duplication syndrome. In a majority of the reported cases where parents have been tested, the duplication seems to have been inherited from a normal parent with minor abnormalities. With this in mind we recommend that family members of patients with a 22q11.2 duplication to be tested for this genetic defect.

  • 31.
    Wentzel, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Lynch, S. A.
    National Centre for Medical Genetics, OLCHC, Dublin, Ireland.
    Stattin, E.-L.
    Department of Medical Biosciences, Medical and Clinical Genetics, Umeå University, Umeå, Sweden.
    Sharkey, F. H.
    Microarray Unit, Cytogenetics Laboratory, Western General Hospital, Edinburgh, UK.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Interstitial Deletions at 6q14.1-q15 Associated with Obesity, Developmental Delay and a Distinct Clinical Phenotype2010In: Molecular Syndromology, ISSN 1661-8769, E-ISSN 1661-8777, Vol. 1, no 2, p. 75-81Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    Interstitial deletions of the long arm of chromosome 6 have been described in several patients with obesity and a Prader-Willi-like phenotype. Haploinsufficiency of the SIM1 gene located at 6q16.3 is suggested as being responsible for the regulation of body weight. Here we report on 2 patients with interstitial deletions at 6q14.1-q15 presenting with obesity and symptoms strikingly similar to those reported for deletions involving the SIM1 gene despite not having a deletion of this gene.

    METHODS

    Array comparative genomic hybridisation was used to diagnose 2 children with obesity and developmental delay, revealing 2 interstitial deletions at 6q14.1-q15 of 8.73 and 4.50 Mb, respectively, and a region of overlap of 4.2-Mb.

    RESULTS

    The similar phenotype in the 2 patients was most likely due to a 4.2-Mb common microdeletion at 6q14.1-q15. Another patient has previously been described with an overlapping deletion. The 3 patients share several features, such as developmental delay, obesity, hernia, rounded face with full cheeks, epicanthal folds, short palpebral fissures, bulbous nose, large ears, and syndactyly between toes II and III.

    CONCLUSIONS

    Together with a previously reported patient, our study suggests that the detected deletions may represent a novel clinically recognisable microdeletion syndrome caused by haploinsufficiency of dosage-sensitive genes in the 6q14.1-q15 region.

  • 32.
    Wentzel, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Rajcan-Separovic, Evica
    Ruivenkamp, Claudia A. L.
    Chantot-Bastaraud, Sandra
    Metay, Corinne
    Andrieux, Joris
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Gijsbers, Antoinet C. J.
    Druart, Luc
    Hyon, Capucine
    Portnoi, Marie-France
    Stattin, Eva-Lena
    Vincent-Delorme, Catherine
    Kant, Sarina G.
    Steinraths, Michelle
    Marlin, Sandrine
    Giurgea, Irina
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p112011In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 19, no 9, p. 959-964Article in journal (Refereed)
    Abstract [en]

    With the clinical implementation of genomic microarrays, the detection of cryptic unbalanced rearrangements in patients with syndromic developmental delay has improved considerably. Here we report the molecular karyotyping and phenotypic description of six new unrelated patients with partially overlapping microdeletions at 10p12.31p11.21 ranging from 1.0 to 10.6 Mb. The smallest region of overlap is 306 kb, which includes WAC gene, known to be associated with microtubule function and to have a role in cell division. Another patient has previously been described with a 10Mb deletion, partially overlapping with our six patients. All seven patients have developmental delay and a majority of the patients have abnormal behaviour and dysmorphic features, including bulbous nasal tip, deep set eyes, synophrys/thick eyebrows and full cheeks, whereas other features varied. All patients also displayed various visual impairments and six out of seven patients had cardiac malformations. Taken together with the previously reported patient, our study suggests that the detected deletions may represent a new contiguous gene syndrome caused by dosage-sensitive genes that predispose to developmental delay.

  • 33. Zambrano, Regina M.
    et al.
    Wohler, Elizabeth
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Cutting, Garry R.
    Batista, Denise A.
    Unbalanced translocation 9;16 in two children with dysmorphic features, and severe developmental delay: Evidence of cross-over within derivative chromosome 9 in patient #12011In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 54, no 2, p. 189-193Article in journal (Refereed)
    Abstract [en]

    We describe 2 children with dysmorphic features, and severe developmental delay presenting with overlapping unbalanced translocations of 9q34.3 and 16p13. Patient #1: A 4 year old African-American female with normal karyotype with a pericentric inversion on one chromosome 9 known to be a benign variant. Low resolution array CGH revealed a single BAC clone loss at 9q34.3 and a single BAC clone gain at 16p13.3, confirmed by FISH. Whole genome SNP array analysis refined these findings, identifying a terminal 1.28 Mb deletion (138,879,862-140,164,310) of 9q34.3 and a terminal 1.62 Mb duplication (45,320-1,621,753) of 16p13.3. Sub-telomeric FISH showed an unbalanced cryptic translocation involving the inverted chromosome 9 and chromosome 16. FISH of the father showed a balanced t(9;16) (q34.3;p13.3) involving the non-inverted chromosome 9, and a pericentric inversion on the normal 9 homologous chromosome. The presence of two rearrangements on chromosome 9, both an unbalanced translocation and a pericentric inversion, indicates recombination between the inverted and derivative 9 homologues from her father. Patient #2: A 1 year old Iraqi-Moroccan female with normal karyotype. Array-CGH identified a 0.56 Mb deletion of 9q34.3 (139,586,637-140,147,760) and an 11.31 Mb duplication of 16p13.3p13.13 (31,010-11,313,519). Maternal FISH showed a balanced t(9;16)(q34.3;p13.13). Both patients present with similar clinical phenotype.

  • 34.
    Zhao, Jin James
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Halvardson, Jonatan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Knaus, Alexej
    Georgii-Hemming, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Institute.
    Baeck, Peter
    Länssjukhuset i Kalmar.
    Krawitz, Peter
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Feuk, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Reduced cell surface levels of GPI-linked markers in a new case with PIGG loss of function2017In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 38, no 10, p. 1394-1401Article in journal (Refereed)
    Abstract [en]

    Glycosylphosphatidylinositol (GPI) is a glycolipid that tethers more than 150 different proteins to the cell surface. Aberrations in biosynthesis of GPI anchors cause congenital disorders of glycosylation with clinical features including intellectual disability (ID), seizures, and facial dysmorphism. Here, we present two siblings with ID, cerebellar hypoplasia, cerebellar ataxia, early-onset seizures, and minor facial dysmorphology. Using exome sequencing, we identified a homozygous nonsense variant (NM_001127178.1:c.1640G>A, p.Trp547*) in the gene Phosphatidylinositol Glycan Anchor Biosynthesis, Class G (PIGG) in both the patients. Variants in several other GPI anchor synthesis genes lead to a reduced expression of GPI-anchored proteins (GPI-APs) that can be measured by flow cytometry. No significant differences in GPI-APs could be detected in patient granulocytes, consistent with recent findings. However, fibroblasts showed a reduced global level of GPI anchors and of specific GPI-linked markers. These findings suggest that fibroblasts might be more sensitive to pathogenic variants in GPI synthesis pathway and are well suited to screen for GPI-anchor deficiencies. Based on genetic and functional evidence, we confirm that pathogenic variants in PIGG cause an ID syndrome, and we find that loss of function of PIGG is associated with GPI deficiency.

  • 35.
    Zhao, Jin James
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Halvardson, Jonatan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zander, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zaghlool, Ammar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Georgii-Hemming, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Karolinska Univ Hosp Solna, Dept Mol Med & Surg, Stockholm, Sweden.
    Månsson, Else
    Örebro Univ Hosp, Dept Pediat, Örebro, Sweden.
    Brandberg, Göran
    Pediat Clin, Falun, Sweden.
    Sävmarker, Helena Ederth
    Gävle Cent Hosp, Dept Pediat, Gävle, Sweden.
    Frykholm, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kuchinskaya, Ekaterina
    Linköping Univ, Dept Clin Genet, Linköping, Sweden.; Linköping Univ, Dept Clin Med, Linköping, Sweden..
    Thuresson, Ann-Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Feuk, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability2018In: American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, ISSN 1552-4841, E-ISSN 1552-485X, Vol. 177, no 1, p. 10-20Article in journal (Refereed)
    Abstract [en]

    Intellectual Disability (ID) is a clinically heterogeneous condition that affects 2-3% of population worldwide. In recent years, exome sequencing has been a successful strategy for studies of genetic causes of ID, providing a growing list of both candidate and validated ID genes. In this study, exome sequencing was performed on 28 ID patients in 27 patient-parent trios with the aim to identify de novo variants (DNVs) in known and novel ID associated genes. We report the identification of 25 DNVs out of which five were classified as pathogenic or likely pathogenic. Among these, a two base pair deletion was identified in the PUF60 gene, which is one of three genes in the critical region of the 8q24.3 microdeletion syndrome (Verheij syndrome). Our result adds to the growing evidence that PUF60 is responsible for the majority of the symptoms reported for carriers of a microdeletion across this region. We also report variants in several genes previously not associated with ID, including a de novo missense variant in NAA15. We highlight NAA15 as a novel candidate ID gene based on the vital role of NAA15 in the generation and differentiation of neurons in neonatal brain, the fact that the gene is highly intolerant to loss of function and coding variation, and previously reported DNVs in neurodevelopmental disorders.

1 - 35 of 35
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