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Welander Distal Myo...
Welander Distal Myopathy Caused by an Ancient Founder Mutation in TIA1 Associated with Perturbed Splicing.
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- Klar, Joakim (author)
- Uppsala universitet,Medicinsk genetik,Science for Life Laboratory, SciLifeLab
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- Sobol, Maria (author)
- Uppsala universitet,Medicinsk genetik,Science for Life Laboratory, SciLifeLab
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- Melberg, Atle (author)
- Uppsala universitet,Neurologi
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- Mäbert, Katrin (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab
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- Ameur, Adam (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Johansson, Anna C V (author)
- Uppsala universitet,Genomik,Science for Life Laboratory, SciLifeLab
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- Feuk, Lars (author)
- Uppsala universitet,Genomik,Science for Life Laboratory, SciLifeLab
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- Entesarian, Miriam (author)
- Karolinska Institutet
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- Örlén, Hanna (author)
- Uppsala universitet,Medicinsk genetik,Science for Life Laboratory, SciLifeLab
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- Casar-Borota, Olivera (author)
- Uppsala universitet,Molekylär och morfologisk patologi,Science for Life Laboratory, SciLifeLab
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- Dahl, Niklas (author)
- Uppsala universitet,Medicinsk genetik,Science for Life Laboratory, SciLifeLab
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(creator_code:org_t)
- Hindawi Limited, 2013
- 2013
- English.
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In: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 34:4, s. 572-577
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Keyword
- Neurology
- Neurologi
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Klar, Joakim
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Sobol, Maria
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Melberg, Atle
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Mäbert, Katrin
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Ameur, Adam
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Johansson, Anna ...
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show more...
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Feuk, Lars
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Entesarian, Miri ...
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Örlén, Hanna
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Casar-Borota, Ol ...
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Dahl, Niklas
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Neurology
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
- Articles in the publication
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Human Mutation
- By the university
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Uppsala University
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Karolinska Institutet