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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.

SUBMITTER: Li X

PROVIDER: S-EPMC4332675 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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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.

Li Xuefu X Zhong Bomeng B Han Weitian W Zhao Ning N Liu Wei W Sui Yu Y Wang Yawen Y Lu Yongping Y Wang Hong H Li Jianxin J Jiang Miao M

PloS one 20150213 2

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 bindin ...[more]

PMID: 25679999

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Project description:BackgroundDistal arthrogryposis (DA) is a group of autosomal dominant skeletal muscle diseases characterized by congenital contractures of distal limb joints. The most common cause of DA is a mutation of the embryonic myosin heavy chain gene, MYH3. Human phenotypes of DA are divided into the weakest form-DA1, a moderately severe form-DA2B (Sheldon-Hall Syndrome), and a severe DA disorder-DA2A (Freeman-Sheldon Syndrome). As models of DA1 and DA2B do not exist, their disease mechanisms are poorly understood.MethodsWe produced the first models of myosin-based DA1 (F437I) and DA2B (A234T) using transgenic Drosophila melanogaster and performed an integrative analysis of the effects of the mutations. Assessments included lifespan, locomotion, ultrastructural analysis, muscle mechanics, ATPase activity, in vitro motility, and protein modeling.ResultsWe observed significant defects in DA1 and DA2B Drosophila flight and jump ability, as well as myofibril assembly and stability, with homozygotes displaying more severe phenotypes than heterozygotes. Notably, DA2B flies showed dramatically stronger phenotypic defects compared to DA1 flies, mirroring the human condition. Mechanical studies of indirect flight muscle fibers from DA1 heterozygotes revealed reduced power output along with increased stiffness and force production, compared to wild-type controls. Further, isolated DA1 myosin showed significantly reduced myosin ATPase activity and in vitro actin filament motility. These data in conjunction with our sinusoidal analysis of fibers suggest prolonged myosin binding to actin and a slowed step associated with Pi release and/or the power stroke. Our results are supported by molecular modeling studies, which indicate that the F437I and A234T mutations affect specific amino acid residue interactions within the myosin motor domain that may alter interaction with actin and nucleotide.ConclusionsThe allele-specific ultrastructural and locomotory defects in our Drosophila DA1 and DA2B models are concordant with the differential severity of the human diseases. Further, the mechanical and biochemical defects engendered by the DA1 mutation reveal that power production, fiber stiffness, and nucleotide handling are aberrant in F437I muscle and myosin. The defects observed in our DA1 and DA2B Drosophila models provide insight into DA phenotypes in humans, suggesting that contractures arise from prolonged actomyosin interactions.

Project description:In the amyoplasia type of arthrogryposis, a reverse pronated grasp pattern is often seen. We hypothesized that repositioning the hands, through distal humerus external rotation osteotomies (DHO), would allow for palm-to-palm grasp without arm cross-over and would improve function and parent/patient satisfaction.The medical records of all patients treated surgically for arthrogryposis were reviewed at the Shriners Hospital for Children, St. Louis, MO. From 2012 to 2014, 9 patients (14 extremities) had undergone a DHO. All patients had preoperative and postoperative video recordings of functional activities and we assessed functional changes after osteotomies. Preoperative upper extremity position was graded as 1, palms facing midline; 2, palm facing posterior; and 3, palms facing away from midline. Postoperative Pediatric Outcomes Data Collection Instrument (PODCI) questionnaires were obtained and parent satisfaction was evaluated.Mean patient age at the time of surgery was 6.5 years. Five patients underwent bilateral DHOs. All patients had 3 or fewer additional procedures on an upper extremity during the study period. All patients had an improved resting posture of the upper extremity after DHO surgery, with a mean change of 51° (range, 15°-90°). Grasp pattern was altered in 13 extremities; there was a change in hand position of at least 1 grade and 5 had complete change from 3 to 1, palms facing away from midline to facing toward midline. There was a wide range in postoperative PODCI scores for function, but Happiness scores were high, mean 89 (range, 60-100). Parents universally stated the procedure improved the child's function "a great deal." There were 2 complications: 1 periprosthetic humerus facture with recurrence of the internal rotation and 1 patient with scarring of the triceps requiring tenolysis.The DHO is an effective procedure for correcting the internal rotation position of the upper extremity in arthrogryposis and the surgery improves hand opposition with minimal complications. Universally, there was perceived improved function with high postoperative PODCI Happiness scores.Therapeutic V.

Dataset Information

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.

Publications

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.

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