Document Detail

Welander Distal Myopathy Caused by an Ancient Founder Mutation in TIA1 Associated with Perturbed Splicing.
MedLine Citation:
PMID:  23348830     Owner:  NLM     Status:  Publisher    
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.
Joakim Klar; Maria Sobol; Atle Melberg; Katrin Mäbert; Adam Ameur; Anna C V Johansson; Lars Feuk; Miriam Entesarian; Hanna Orlén; Olivera Casar-Borota; Niklas Dahl
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-24
Journal Detail:
Title:  Human mutation     Volume:  -     ISSN:  1098-1004     ISO Abbreviation:  Hum. Mutat.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9215429     Medline TA:  Hum Mutat     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2013 Wiley Periodicals, Inc.
Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory and Science for Life Laboratory, Uppsala University, 751 85, Uppsala, Sweden.
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