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Klar, J., Ali, Z., Farooq, M., Khan, K., Wikström, J., Iqbal, M., . . . Dahl, N. (2017). A missense variant in ITPR1 provides evidence for autosomal recessive SCA29 with asymptomatic cerebellar hypoplasia in carriers.. European Journal of Human Genetics, 25(7), 848-853
Open this publication in new window or tab >>A missense variant in ITPR1 provides evidence for autosomal recessive SCA29 with asymptomatic cerebellar hypoplasia in carriers.
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2017 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 25, no 7, p. 848-853Article in journal (Refereed) Published
Abstract [en]

Spinocerebellar ataxias (SCA) comprise a heterogeneous group of inherited neurological disorders characterized by a range of symptoms from both cerebellar and extra cerebellar structures. We investigated the cause of autosomal recessive, congenital SCA in six affected family members from a large consanguineous family. Using whole-exome sequencing, we identified a homozygous ITPR1 missense variant [c.5360T>C; p.(L1787P)] segregating in all affected individuals. Heterozygous carriers were asymptomatic despite cerebellar hypoplasia. Variants in the ITPTR1 gene have previously been associated exclusively with autosomal dominant SCA15 and SCA29 with slow or no progression. The L1787 residue is highly conserved and the leucine to proline substitution has a predicted destabilizing effect on the protein structure. Additionally, the L1787P variant is located in a domain separated from previously described and dominant-acting missense variants consistent with a distinct effect on IP3R1 tetramer structure and function. Taken together, we show for the first time that a biallelic ITPR1 missense variant may cause an autosomal recessive and infantile onset SCA29, albeit with subclinical cerebellar hypoplasia in carriers. Our findings add to the genetic complexity of SCA29 and broaden the correlations between ITPR1 variants and their clinical expression.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-322151 (URN)10.1038/ejhg.2017.54 (DOI)000403061300013 ()28488678 (PubMedID)
Funder
Swedish Research Council, 2015-02424Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2017-05-16 Created: 2017-05-16 Last updated: 2017-08-25Bibliographically approved
Klar, J., Piontek, J., Milatz, S., Tariq, M., Jameel, M., Breiderhoff, T., . . . Dahl, N. (2017). Altered paracellular cation permeability due to a rare CLDN10B variant causes anhidrosis and kidney damage. PLoS Genetics, 13(7), Article ID e1006897.
Open this publication in new window or tab >>Altered paracellular cation permeability due to a rare CLDN10B variant causes anhidrosis and kidney damage
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2017 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 7, article id e1006897Article in journal (Refereed) Published
Abstract [en]

Claudins constitute the major component of tight junctions and regulate paracellular permeability of epithelia. Claudin-10 occurs in two major isoforms that form paracellular channels with ion selectivity. We report on two families segregating an autosomal recessive disorder characterized by generalized anhidrosis, severe heat intolerance and mild kidney failure. All affected individuals carry a rare homozygous missense mutation c.144C>G, p.(N48K) specific for the claudin-10b isoform. Immunostaining of sweat glands from patients suggested that the disease is associated with reduced levels of claudin-10b in the plasma membranes and in canaliculi of the secretory portion. Expression of claudin-10b N48K in a 3D cell model of sweat secretion indicated perturbed paracellular Na+ transport. Analysis of paracellular permeability revealed that claudin-10b N48K maintained cation over anion selectivity but with a reduced general ion conductance. Furthermore, freeze fracture electron microscopy showed that claudin-10b N48K was associated with impaired tight junction strand formation and altered cis-oligomer formation. These data suggest that claudin-10b N48K causes anhidrosis and our findings are consistent with a combined effect from perturbed TJ function and increased degradation of claudin-10b N48K in the sweat glands. Furthermore, affected individuals present with Mg2+ retention, secondary hyperparathyroidism and mild kidney failure that suggest a disturbed reabsorption of cations in the kidneys. These renal-derived features recapitulate several phenotypic aspects detected in mice with kidney specific loss of both claudin-10 isoforms. Our study adds to the spectrum of phenotypes caused by tight junction proteins and demonstrates a pivotal role for claudin-10b in maintaining paracellular Na+ permeability for sweat production and kidney function.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-339175 (URN)10.1371/journal.pgen.1006897 (DOI)000406615300034 ()28686597 (PubMedID)
Funder
Swedish Research Council, 2015-02424Swedish Society for Medical Research (SSMF)
Available from: 2018-01-17 Created: 2018-01-17 Last updated: 2018-02-02Bibliographically approved
Ali, Z., Zulfiqar, S., Klar, J., Wikström, J., Ullah, F., Khan, A., . . . Dahl, N. (2017). 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 features. BMC Medical Genetics, 18(1), Article ID 144.
Open this publication in new window or tab >>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 features
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2017 (English)In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 18, no 1, article id 144Article in journal (Refereed) Published
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.

Keyword
3D protein modeling, Cerebellar syndrome, Cerebral atrophy, Developmental delay, GRID2 gene, GluD2, Mutation, Whole exome sequencing
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-336718 (URN)10.1186/s12881-017-0504-6 (DOI)000417599400001 ()29207948 (PubMedID)
Funder
Swedish Research Council, 2015-02424Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

Zafar Ali, Shumaila Zulfiqar and Joakim Klar contributed equally

Available from: 2017-12-15 Created: 2017-12-15 Last updated: 2018-03-07Bibliographically approved
Angsten, G., Gustafson, E., Dahl, N. & Christofferson, R. H. (2017). Resolution of infantile intestinal pseudo-obstruction in a boy. Journal of Osteoporosis and Physical Activity, 24, 28-34
Open this publication in new window or tab >>Resolution of infantile intestinal pseudo-obstruction in a boy
2017 (English)In: Journal of Osteoporosis and Physical Activity, ISSN 2052-3211, E-ISSN 2213-5766, Vol. 24, p. 28-34Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Elsevier, 2017
Keyword
Child, Intestinal pseudo-obstruction, Home parenteral nutrition, Unsaturated fatty acid parenteral nutrition, Taurolidine, Outcome
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-335647 (URN)10.1016/j.epsc.2017.06.007 (DOI)000409098900008 ()
Available from: 2017-12-08 Created: 2017-12-08 Last updated: 2017-12-08Bibliographically approved
Stattin, E., Henning, P., Klar, J., McDermott, E., Stecksen-Blicks, C., Sandström, P.-E., . . . Lerner, U. H. (2017). SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts.. Scientific Reports, 7, Article ID 3012.
Open this publication in new window or tab >>SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts.
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 3012Article in journal (Refereed) Published
Abstract [en]

Autosomal recessive osteopetrosis (ARO) is a heterogeneous disorder, characterized by defective osteoclastic resorption of bone that results in increased bone density. We have studied nine individuals with an intermediate form of ARO, from the county of Västerbotten in Northern Sweden. All afflicted individuals had an onset in early infancy with optic atrophy, and in four patients anemia was present at diagnosis. Tonsillar herniation, foramen magnum stenosis, and severe osteomyelitis of the jaw were common clinical features. Whole exome sequencing, verified by Sanger sequencing, identified a splice site mutation c.212 + 1 G > T in the SNX10 gene encoding sorting nexin 10. Sequence analysis of the SNX10 transcript in patients revealed activation of a cryptic splice site in intron 4 resulting in a frame shift and a premature stop (p.S66Nfs * 15). Haplotype analysis showed that all cases originated from a single mutational event, and the age of the mutation was estimated to be approximately 950 years. Functional analysis of osteoclast progenitors isolated from peripheral blood of patients revealed that stimulation with receptor activator of nuclear factor kappa-B ligand (RANKL) resulted in a robust formation of large, multinucleated osteoclasts which generated sealing zones; however these osteoclasts exhibited defective ruffled borders and were unable to resorb bone in vitro.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-325569 (URN)10.1038/s41598-017-02533-2 (DOI)000402879800068 ()28592808 (PubMedID)
Funder
Swedish Research CouncilSwedish Rheumatism Association
Available from: 2017-06-26 Created: 2017-06-26 Last updated: 2017-09-06Bibliographically approved
Bergendal, B., Norderyd, J., Zhou, X., Klar, J. & Dahl, N. (2016). Abnormal primary and permanent dentitions with ectodermal symptoms predict WNT10A deficiency. BMC Medical Genetics, 17, Article ID 88.
Open this publication in new window or tab >>Abnormal primary and permanent dentitions with ectodermal symptoms predict WNT10A deficiency
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2016 (English)In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 17, article id 88Article in journal (Refereed) Published
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.

Keyword
WNT10A mutations, Ectodermal dysplasia, Dental, Primary dentition, Permanent dentition
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-312069 (URN)10.1186/s12881-016-0349-4 (DOI)000389277800001 ()27881089 (PubMedID)
Funder
Swedish Research Council, 2015-02424Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2017-01-04 Created: 2017-01-04 Last updated: 2018-01-13Bibliographically approved
Halim, D., Hofstra, R. M. W., Signorile, L., Verdijk, R. M., van der Werf, C. S., Sribudiani, Y., . . . Alves, M. M. (2016). ACTG2 variants impair actin polymerization in sporadic Megacystis Microcolon Intestinal Hypoperistalsis Syndrome. Human Molecular Genetics, 25(3), 571-583
Open this publication in new window or tab >>ACTG2 variants impair actin polymerization in sporadic Megacystis Microcolon Intestinal Hypoperistalsis Syndrome
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2016 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 3, p. 571-583Article in journal (Refereed) Published
Abstract [en]

Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS) is a rare congenital disorder, in which heterozygous missense variants in the Enteric Smooth Muscle actin gamma-2 (ACTG2) gene have been recently identified. To investigate the mechanism by which ACTG2 variants lead to MMIHS, we screened a cohort of eleven MMIHS patients, eight sporadic and three familial cases, and performed immunohistochemistry, molecular modeling and molecular dynamics (MD) simulations, and in vitro assays. In all sporadic cases, a heterozygous missense variant in ACTG2 was identified. ACTG2 expression was detected in all intestinal layers where smooth muscle cells are present in different stages of human development. No histopathological abnormalities were found in the patients. Using molecular modeling and MD simulations, we predicted that ACTG2 variants lead to significant changes to the protein function. This was confirmed by in vitro studies, which showed that the identified variants not only impair ACTG2 polymerization, but also contribute to reduced cell contractility. Taken together, our results confirm the involvement of ACTG2 in sporadic MMIHS, and bring new insights to MMIHS pathogenesis.

National Category
Medical Genetics Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-283793 (URN)10.1093/hmg/ddv497 (DOI)000372149500013 ()26647307 (PubMedID)
Available from: 2016-04-14 Created: 2016-04-14 Last updated: 2018-01-10Bibliographically approved
Kele, M., Day, K., Ronnholm, H., Schuster, J., Dahl, N. & Falk, A. (2016). Generation of human iPS cell line CTL07-II from human fibroblasts, under defined and xeno-free conditions. Stem Cell Research, 17(3), 474-478
Open this publication in new window or tab >>Generation of human iPS cell line CTL07-II from human fibroblasts, under defined and xeno-free conditions
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2016 (English)In: Stem Cell Research, ISSN 1873-5061, E-ISSN 1876-7753, Vol. 17, no 3, p. 474-478Article in journal (Refereed) Published
Abstract [en]

CTL07-II is a healthy feeder-free and characterized human induced pluripotent stem (iPS) cell line. Cultured under xeno-free and defined conditions. The line is generated from healthy human fibroblasts with non-integrating Sendai virus vectors encoding the four Yamanaka factors, OCT4, SOX2, KLF4 and cMYC. The generated iPS cells are free from reprogramming vectors and their purity, karyotypic stability and pluripotent capacity is confirmed.

National Category
Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-317059 (URN)10.1016/j.scr.2016.09.028 (DOI)000393191300004 ()27789397 (PubMedID)
Available from: 2017-03-28 Created: 2017-03-28 Last updated: 2018-01-13Bibliographically approved
Ali, Z., Klar, J., Jameel, M., Khan, K., Fatima, A., Raininko, R., . . . Dahl, N. (2016). Novel SACS mutations associated with intellectual disability, epilepsy and widespread supratentorial abnormalities. Journal of the Neurological Sciences, 371, 105-111
Open this publication in new window or tab >>Novel SACS mutations associated with intellectual disability, epilepsy and widespread supratentorial abnormalities
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2016 (English)In: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 371, p. 105-111Article in journal (Refereed) Published
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.

National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-309036 (URN)10.1016/j.jns.2016.10.032 (DOI)000389399300024 ()27871429 (PubMedID)
Funder
Swedish Research Council, 2015-02424Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2016-12-01 Created: 2016-12-01 Last updated: 2017-11-29Bibliographically approved
Finnsson, J., Sundblom, J., Dahl, N., Melberg, A. & Raininko, R. (2015). LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course. Annals of Neurology, 78(3), 412-25
Open this publication in new window or tab >>LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course
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2015 (English)In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 78, no 3, p. 412-25Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Duplication of the LMNB1 gene encoding lamin B1 causes adult-onset autosomal-dominant leukodystrophy (ADLD) starting with autonomic symptoms, which are followed by pyramidal signs and ataxia. Magnetic resonance imaging (MRI) of the brain reveals characteristic findings. This is the first longitudinal study on this disease. Our objective is to describe the natural clinical and radiological course of LMNB1-related ADLD.

METHODS: Twenty-three subjects in two families with LMNB1 duplications were studied over two decades with clinical assessment and MRI of the brain and spinal cord. They were 29 to 70 years old at their first MRI. Repeated MRIs were performed in 14 subjects over a time period of up to 17 years.

RESULTS: Pathological MRI findings were found in the brain and spinal cord in all examinations (i.e., even preceding clinical symptoms). MRI changes and clinical symptoms progressed in a definite order. Autonomic dysfunction appeared in the fifth to sixth decade, preceding or together with gait and coordination difficulties. Motor signs developed ascending from spastic paraplegia to tetraplegia and pseudobulbar palsy in the seventh decade. There were clinical, radiological, and neurophysiological signs of myelopathy. Survival lasted more than two decades after clinical onset.

INTERPRETATION: LMNB1-related ADLD is a slowly progressive neurological disease. MRI abnormalities of the brain and spinal cord can precede clinical symptoms by more than a decade and are extensive in all symptomatic patients. Spinal cord involvement is a likely contributing factor to early autonomic symptoms and spastic paraplegia. Ann Neurol 2015;78:412-425.

National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-261207 (URN)10.1002/ana.24452 (DOI)000360218800008 ()26053668 (PubMedID)
Note

Atle Melberg och Raili Raininko delar sistaförfattarskapet.

Available from: 2015-08-31 Created: 2015-08-31 Last updated: 2018-01-11Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-8122-0800

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