Welander distal myopathy is caused by a mutation in the RNA-binding protein TIA1
Article first published online: 11 FEB 2013
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 73, Issue 4, pages 500–509, April 2013
How to Cite
Hackman, P., Sarparanta, J., Lehtinen, S., Vihola, A., Evilä, A., Jonson, P. H., Luque, H., Kere, J., Screen, M., Chinnery, P. F., Åhlberg, G., Edström, L. and Udd, B. (2013), Welander distal myopathy is caused by a mutation in the RNA-binding protein TIA1. Ann Neurol., 73: 500–509. doi: 10.1002/ana.23831
- Issue published online: 21 MAY 2013
- Article first published online: 11 FEB 2013
- Accepted manuscript online: 13 DEC 2012 04:43AM EST
- Manuscript Accepted: 30 NOV 2012
- Manuscript Revised: 14 OCT 2012
- Manuscript Received: 14 AUG 2012
- Sigrid Jusélius Foundation, Helsinki University Hospital (EVO research funds)
- Vaasa Central Hospital Research Funds, Finska Läkaresällskapet, and Folkhälsan Research Foundation (B.U.)
- Alfred Kordelin Foundation and Lihastautien tutkimussäätiö (J.S.)
- Wellcome Trust Centre for Mitochondrial Research . Grant Number: 096919Z/11/Z
- Medical Research Council (UK) Centre for Translational Muscle Disease research, Association Française contre les Myopathies . Grant Number: EU FP7 TIRCON
- National Institute for Health Research (NIHR)
A study was undertaken to identify the molecular cause of Welander distal myopathy (WDM), a classic autosomal dominant distal myopathy.
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.
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.
WDM is caused by mutated TIA1 through a dominant pathomechanism probably involving altered stress granule dynamics. Ann Neurol 2013;73:500–509