title: Two novel mutations in myosin binding protein C slow causing distal arthrogryposis type 2 in two large Han Chinese families may suggest important functional role of immunoglobulin domain C2.
abstract: Distal arthrogryposes (DAs) are a group of disorders that mainly involve the distal parts of the limbs and at least ten different DAs have been described to date. DAs are mostly described as autosomal dominant disorders with variable expressivity and incomplete penetrance, but recently autosomal recessive pattern was reported in distal arthrogryposis type 5D. Mutations in the contractile genes are found in about 50% of all DA patients. Of these genes, mutations in the gene encoding myosin binding protein C slow MYBPC1 were recently identified in two families with distal arthrogryposis type 1B. Here, we described two large Chinese families with autosomal dominant distal arthrogryposis type 2(DA2) with incomplete penetrance and variable expressivity. Some unique overextension contractures of the lower limbs and some distinctive facial features were present in our DA2 pedigrees. We performed follow-up DNA sequencing after linkage mapping and first identified two novel MYBPC1 mutations (c.1075G>A [p.E359K] and c.956C>T [p.P319L]) responsible for these Chinese DA2 families of which one introduced by germline mosacism. Each mutation was found to cosegregate with the DA2 phenotype in each family but not in population controls. Both substitutions occur within C2 immunoglobulin domain, which together with C1 and the M motif constitute the binding site for the S2 subfragment of myosin. Our results expand the phenotypic spectrum of MYBPC1-related arthrogryposis multiplex congenita (AMC). We also proposed the possible molecular mechanisms that may underlie the pathogenesis of DA2 myopathy associated with these two substitutions in MYBPC1.
authors: Key Laboratory of Reproductive Health of Liaoning Province, Shenyang, China.
authors: Xuefu
authors: X
authors: Li
authors: Emergency department, Nanjing First Hospital, Nanjing, China.
authors: Bomeng
authors: B
authors: Zhong
authors: Key Laboratory of Reproductive Health of Liaoning Province, Shenyang, China.
authors: Weitian
authors: W
authors: Han
authors: Key Laboratory of Reproductive Health of Liaoning Province, Shenyang, China.
authors: Ning
authors: N
authors: Zhao
authors: Key Laboratory of Reproductive Health of Liaoning Province, Shenyang, China.
authors: Wei
authors: W
authors: Liu
authors: Key Laboratory of Reproductive Health of Liaoning Province, Shenyang, China.
authors: Yu
authors: Y
authors: Sui
authors: Key Laboratory of Reproductive Health of Liaoning Province, Shenyang, China.
authors: Yawen
authors: Y
authors: Wang
authors: Key Laboratory of Reproductive Health of Liaoning Province, Shenyang, China.
authors: Yongping
authors: Y
authors: Lu
authors: Key Laboratory of Reproductive Health of Liaoning Province, Shenyang, China.
authors: Hong
authors: H
authors: Wang
authors: Key Laboratory of Reproductive Health of Liaoning Province, Shenyang, China.
authors: Jianxin
authors: J
authors: Li
authors: Key Laboratory of Reproductive Health of Liaoning Province, Shenyang, China.
authors: Miao
authors: M
authors: Jiang
mesh_terms: D000595:Amino Acid Sequence; D001176:Arthrogryposis / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D044466:Asian People; D002352:Carrier Proteins / Q000235:genetics*; D002681:China; D003598:Cytoskeletal Proteins / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D008297:Male; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D016415:Sequence Alignment; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D007136:Immunoglobulins; D000099163:Myosin Binding Protein C; C510594:MYH3 polypeptide, human