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Welander Distal Myopathy Caused by an Ancient Founder Mutation in TIA1 Associated with Perturbed Splicing.
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.ORCID iD: 0000-0003-4185-7409
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2013 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 34, no 4, 572-577 p.Article in journal (Refereed) Published
Abstract [en]

Welander distal myopathy (WDM) is an adult onset autosomal dominant disorder characterized by distal limb weakness which progresses slowly from the fifth decade. All WDM patients are of Swedish or Finnish descent and share a rare chromosome 2p13 haplotype. We restricted the WDM associated haplotype followed by whole exome sequencing. Within the conserved haplotype we identified a single heterozygous mutation c.1150G>A (p.E384K) in TIA1 in all WDM patients investigated (n = 43). The TIA1 protein regulates splicing and translation through direct interaction with mRNA and the p.E384K mutation is located in the C-terminal Q-rich domain that interacts with the U1-C splicing factor. TIA1 has been shown to prevent skipping of SMN2 exon 7 and we show that WDM patients have increased levels of spliced SMN2 in skeletal muscle cells when compared to controls. Immunostaining of WDM muscle biopsies showed accumulation of TIA1 and stress granulae proteins adjacent to intracellular inclusions, a typical finding in WDM. The combined findings strongly suggest that the TIA1 mutation causes perturbed RNA splicing and cellular stress resulting in WDM. The selection against the mutation is likely to be negligible and the age of the TIA1 founder mutation was calculated to approximately 1050 years, which coincides with the epoch of early seafaring across the Baltic Sea.

Place, publisher, year, edition, pages
2013. Vol. 34, no 4, 572-577 p.
National Category
Neurology
Research subject
Neurology
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URN: urn:nbn:se:uu:diva-197333DOI: 10.1002/humu.22282ISI: 000316629000005PubMedID: 23348830OAI: oai:DiVA.org:uu-197333DiVA: diva2:612581
Available from: 2013-03-22 Created: 2013-03-22 Last updated: 2017-12-06Bibliographically approved

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Klar, JoakimSobol, MariaMelberg, AtleAmeur, AdamJohansson, Anna C VFeuk, LarsÖrlén, HannaCasar-Borota, OliveraDahl, Niklas

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Klar, JoakimSobol, MariaMelberg, AtleAmeur, AdamJohansson, Anna C VFeuk, LarsÖrlén, HannaCasar-Borota, OliveraDahl, Niklas
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Medical GeneticsScience for Life Laboratory, SciLifeLabNeurologyDepartment of Immunology, Genetics and PathologyGenomicsMolecular and Morphological Pathology
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