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.

Novel mutations in MYBPC1 are associated with myogenic tremor and mild myopathy

“…15,16 In addition to binding LMM, the COOH terminus of sMyBP-C supports binding to titin, obscurin, four and a half LIM domains 1 (FHL1) protein, and creatine kinase. [20][21][22] Here, we report on a distinct clinical phenotype in two independent, three-generation families, manifesting as mild myopathy invariably associated with a persistent, posturally pronounced, high-frequency tremor in all affected individuals that segregates with novel, dominant, missense mutations in MYBPC1 in each family. (DA).…”

Thick Filament Protein Network, Functions, and Disease Association

“…Recently, dominant missense mutations in MYBPC1 , which encodes sMyBP-C, have been linked to both distal arthrogryposis type-1 (DA-1) and distal arthrogryposis type-2 (DA-2) (15,214,325). DA-1 affects approximately 1 in 10,000 individuals and results in contractures often limited to distal muscles of the hands and feet.…”

“…Two novel autosomal dominant missense mutations residing in Ig domain C2, Pro319Leu and Glu359Lys, were also linked to DA-2 (325). DA-2 is a more severe form of DA, which is also characterized by contractures of the hands and feet, but is often accompanied by mild to severe craniofacial anomalies and/or scoliosis (35, 300).…”

Skeletal myosin binding protein-C: An increasingly important regulator of striated muscle physiology

“…Additional mutations in MYBPC1 have been identified in two Chinese families with DA type 2 (DA2) [91]. The DA2 subtype is similar to that of DA1, with camptodactyly and ulnar deviation, but with additional facial and pharyngeal involvement [92].…”

“…This mutation, E186K, occurs at the border of the C1- and M-domains, a region expected to contribute to both actin and myosin binding [95]. Unlike the other missense mutations described in MYBPC1 above [87, 91], individuals harboring a heterozygous mutation were unaffected, thus becoming the first non-lethal autosomal recessive MYBPC1 mutation. Excitingly, two novel mutations in MYBPC1 have recently been described, resulting in Y248H and E248K substitutions, respectively.…”