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W elander Distal Myopathy Caused by an Ancient Founder Mutation in TIA1 Associated with Perturbed Splicing
Author(s) -
Klar Joakim,
Sobol Maria,
Melberg Atle,
Mäbert Katrin,
Ameur Adam,
Johansson Anna C.V.,
Feuk Lars,
Entesarian Miriam,
Örlén Hanna,
CasarBorota Olivera,
Dahl Niklas
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22282
Subject(s) - biology , rna splicing , exon , haplotype , mutation , genetics , exome sequencing , rna binding protein , microbiology and biotechnology , gene , rna , genotype
W elander 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 S wedish or F innish 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.1150 G > A (p. E 384 K ) in T‐cell intracellular antigen‐1 ( TIA1 ) in all WDM patients investigated ( n = 43). The TIA 1 protein regulates splicing, and translation through direct interaction with m RNA and the p. E 384 K mutation is located in the C ‐terminal Q ‐rich domain that interacts with the U 1‐ C splicing factor. TIA 1 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 with controls. Immunostaining of WDM muscle biopsies showed accumulation of TIA 1 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 1,050 years, which coincides with the epoch of early seafaring across the B altic S ea.