Myosin binding protein C1: a novel gene for autosomal dominant distal arthrogryposis type 1.
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.
Gurnett
Christina A
CA
Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA. gurnettc@neuro.wustl.edu
Desruisseau
David M
DM
McCall
Kevin
K
Choi
Ryan
R
Meyer
Zachary I
ZI
Talerico
Michael
M
Miller
Sara E
SE
Ju
Jeong-Sun
JS
Pestronk
Alan
A
Connolly
Anne M
AM
Druley
Todd E
TE
Weihl
Conrad C
CC
Dobbs
Mathew B
MB
D001176:Arthrogryposis / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D000099163:Myosin Binding Protein C
D002352:Carrier Proteins; D000099163:Myosin Binding Protein C