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- Title
Myosin binding protein C1: a novel gene for autosomal dominant distal arthrogryposis type 1.
- Authors
Gurnett, Christina A; Desruisseau, David M; McCall, Kevin; Choi, Ryan; Meyer, Zachary I; Talerico, Michael; Miller, Sara E; Ju, Jeong-Sun; Pestronk, Alan; Connolly, Anne M; Druley, Todd E; Weihl, Conrad C; Dobbs, Mathew B
- Abstract
Distal arthrogryposis type I (DA1) is a disorder characterized by congenital contractures of the hands and feet for which few genes have been identified. Here we describe a five-generation family with DA1 segregating as an autosomal dominant disorder with complete penetrance. Genome-wide linkage analysis using Affymetrix GeneChip Mapping 10K data from 12 affected members of this family revealed a multipoint LOD(max) of 3.27 on chromosome 12q. Sequencing of the slow-twitch skeletal muscle myosin binding protein C1 (MYBPC1), located within the linkage interval, revealed a missense mutation (c.706T>C) that segregated with disease in this family and causes a W236R amino acid substitution. A second MYBPC1 missense mutation was identified (c.2566T>C)(Y856H) in another family with DA1, accounting for an MYBPC1 mutation frequency of 13% (two of 15). Skeletal muscle biopsies from affected patients showed type I (slow-twitch) fibers were smaller than type II fibers. Expression of a green fluorescent protein (GFP)-tagged MYBPC1 construct containing WT and DA1 mutations in mouse skeletal muscle revealed robust sarcomeric localization. In contrast, a more diffuse localization was seen when non-fused GFP and MYBPC1 proteins containing corresponding MYBPC3 amino acid substitutions (R326Q, E334K) that cause hypertrophic cardiomyopathy were expressed. These findings reveal that the MYBPC1 is a novel gene responsible for DA1, though the mechanism of disease may differ from how some cardiac MYBPC3 mutations cause hypertrophic cardiomyopathy.
- Publication
Human molecular genetics, 2010, Vol 19, Issue 7, p1165
- ISSN
1460-2083
- Publication type
Journal Article
- DOI
10.1093/hmg/ddp587