title: Welander distal myopathy is caused by a mutation in the RNA-binding protein TIA1.
abstract: OBJECTIVE
  A study was undertaken to identify the molecular cause of Welander distal myopathy (WDM), a classic autosomal dominant distal myopathy.
  
  
  METHODS
  The genetic linkage was confirmed and defined by microsatellite and single nucleotide polymorphism haplotyping. The whole linked genomic region was sequenced with targeted high-throughput and Sanger sequencing, and coding transcripts were sequenced on the cDNA level. WDM muscle biopsies were studied by Western blotting and immunofluorescence microscopy. Splicing of TIA1 and its target genes in muscle and myoblast cultures was analyzed by reverse transcriptase polymerase chain reaction. Mutant TIA1 was characterized by cell biological studies on HeLa cells, including quantification of stress granules by high content analysis and fluorescence recovery after photobleaching (FRAP) experiments.
  
  
  RESULTS
  The linked haplotype at 2p13 was narrowed down to <806 kb. Sequencing by multiple methods revealed only 1 segregating coding mutation, c.1362 G>A (p.E384K) in the RNA-binding protein TIA1, a key component of stress granules. Immunofluorescence microscopy of WDM biopsies showed a focal increase of TIA1 in atrophic and vacuolated fibers. In HeLa cells, mutant TIA1 constructs caused a mild increase in stress granule abundance compared to wild type, and showed slower average fluorescence recovery in FRAP.
  
  
  CONCLUSIONS
  WDM is caused by mutated TIA1 through a dominant pathomechanism probably involving altered stress granule dynamics.
authors: Folkhälsan Institute of Genetics and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors: Peter
authors: P
authors: Hackman
authors: Jaakko
authors: J
authors: Sarparanta
authors: Sara
authors: S
authors: Lehtinen
authors: Anna
authors: A
authors: Vihola
authors: Anni
authors: A
authors: Evilä
authors: Per Harald
authors: PH
authors: Jonson
authors: Helena
authors: H
authors: Luque
authors: Juha
authors: J
authors: Kere
authors: Mark
authors: M
authors: Screen
authors: Patrick F
authors: PF
authors: Chinnery
authors: Gabrielle
authors: G
authors: Åhlberg
authors: Lars
authors: L
authors: Edström
authors: Bjarne
authors: B
authors: Udd
mesh_terms: D002478:Cells, Cultured; D049310:Distal Myopathies / Q000235:genetics*; D005260:Female; D036681:Fluorescence Recovery After Photobleaching; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D038761:Photobleaching; D039102:Poly(A)-Binding Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D000074019:T-Cell Intracellular Antigen-1; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D039102:Poly(A)-Binding Proteins; D011506:Proteins; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; D025801:Ubiquitin; D049452:Green Fluorescent Proteins