title: Myosin binding protein C1: a novel gene for autosomal dominant distal arthrogryposis type 1.
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.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA. gurnettc@neuro.wustl.edu
authors.forename: Christina A
authors.initials: CA
authors.lastname: Gurnett
authors.forename: David M
authors.initials: DM
authors.lastname: Desruisseau
authors.forename: Kevin
authors.initials: K
authors.lastname: McCall
authors.forename: Ryan
authors.initials: R
authors.lastname: Choi
authors.forename: Zachary I
authors.initials: ZI
authors.lastname: Meyer
authors.forename: Michael
authors.initials: M
authors.lastname: Talerico
authors.forename: Sara E
authors.initials: SE
authors.lastname: Miller
authors.forename: Jeong-Sun
authors.initials: JS
authors.lastname: Ju
authors.forename: Alan
authors.initials: A
authors.lastname: Pestronk
authors.forename: Anne M
authors.initials: AM
authors.lastname: Connolly
authors.forename: Todd E
authors.initials: TE
authors.lastname: Druley
authors.forename: Conrad C
authors.initials: CC
authors.lastname: Weihl
authors.forename: Mathew B
authors.initials: MB
authors.lastname: Dobbs
mesh_terms: 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
chemical_list: D002352:Carrier Proteins; D000099163:Myosin Binding Protein C