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Welander distal myopathy is caused by a mutation in the RNA-binding protein TIA1

Lookup NU author(s): Professor Patrick Chinnery

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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. Interpretation WDM is caused by mutated TIA1 through a dominant pathomechanism probably involving altered stress granule dynamics. Ann Neurol 2013;73:500-509

Publication metadata

Author(s): Hackman P, Sarparanta J, Lehtinen S, Vihola A, Evila A, Jonson PH, Luque H, Kere J, Screen M, Chinnery PF, Ahlberg G, Edstrom L, Udd B

Publication type: Article

Publication status: Published

Journal: Annals of Neurology

Year: 2013

Volume: 73

Issue: 4

Pages: 500-509

Print publication date: 01/04/2013

Online publication date: 11/02/2013

Acceptance date: 30/11/2012

ISSN (print): 0364-5134

ISSN (electronic): 1531-8249

Publisher: John Wiley & Sons, Inc.

URL: http://dx.doi.org/10.1002/ana.23831

DOI: 10.1002/ana.23831

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Funding

Funder referenceFunder name
EU
Finska Lakaresallskapet
Folkhalsan Research Foundation
Liv och Halsa Foundation
National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust and Newcastle University
Sigrid Juselius Foundation
Academy of Finland and Sigrid Juselius Foundation
Alfred Kordelin Foundation
Department of Clinical Neuroscience, Karolinska Institute
Helsinki University Hospital (EVO research funds)
Lihastautien tutkimussaatio
Medical Research Council (UK) Centre for Translational Muscle Disease research, Association Franc,aise contre les Myopathies
Oskar Oflund Foundation and Association Francaise contre les Myopathies
Vaasa Central Hospital Research Funds
096919Z/11/ZWellcome Trust Centre for Mitochondrial Research

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