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.

Genetic Abnormalities in a Calf with Congenital Increased Muscular Tonus

“…It has both structural and regulatory roles in muscle function, providing thick filament stability and modulating contractility through interactions with myosin and actin (OMIM 160794). In humans, two mutations in MYBPC1 have been found to cause autosomal dominant distal arthrogryposis type 1, a condition characterized by contractures in the hands and feet 14. Both mutations are SNPs resulting in amino acid exchanges (p.Trp236Arg and p.Tyr856His respectively; Fig 2C).…”

Skeletal Muscle Abnormalities and Genetic Factors Related to Vertical Talus

“…An exception to this uncertainty is in the case of distal arthrogryposis, a limb contracture syndrome in which vertical talus is a common feature [15]. Distal arthrogryposis is associated with skeletal muscle abnormalities resulting from sarcomere gene mutations [5,15].…”

“…An exception to this uncertainty is in the case of distal arthrogryposis, a limb contracture syndrome in which vertical talus is a common feature [15]. Distal arthrogryposis is associated with skeletal muscle abnormalities resulting from sarcomere gene mutations [5,15]. As the phenotype of distal arthrogryposis is similar to that of isolated vertical talus, we chose to investigate whether similar skeletal muscle abnormalities are present in muscle biopsy specimens of a subset of patients with vertical talus (six of whom had idiopathic vertical talus).…”

“…Although these skeletal muscle morphologic variations are not specific for any one disease, they are common in congenital myopathies and distal arthrogryposis [18]. One patient with distal arthrogryposis type 1 (DA1) [15], vertical talus, and a mutation in skeletal muscle myosin binding protein C1 (MYBPC1) was included in this series. His biopsy specimen characteristically showed type I fiber atrophy.…”

Knockdown of fast skeletal myosin-binding protein C in zebrafish results in a severe skeletal myopathy

“…Recently, mutations in slow skeletal MyBPC-1 have been linked to skeletal myopathy (Gurnett et al, 2010;Markus et al, 2012), and mRNA injection of mutated MyBPC-1 in zebrafish has been shown to induce structural defects in muscle (Ha et al, 2013). To our knowledge, the fast skeletal MyBPC-2 has not been linked to disease, and no specific transgenic mouse models are available.…”