Arthrogryposis, Distal, Type 1b

A number sign (#) is used with this entry because of evidence that distal arthrogryposis type 1B (DA1B) is caused by heterozygous mutation in the MYBPC1 gene (160794) on chromosome 12q23.

For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1A (108120).

Clinical Features

Gurnett et al. (2010) described a 5-generation family in which 12 members had distal arthrogryposis type 1. Nine of the 12 had congenital talipes equinovarus (clubfoot) and the 3 others had congenital vertical talus. The lower limb contractures were bilateral in all cases except 1 female with left-sided clubfoot and 1 female with right-sided clubfoot. Five of the 12 had hand contractures manifesting as either camptodactyly and ulnar deviation of the fingers (3 individuals) or extension contracture of the fourth digit (2 individuals). The other 7 had no evidence of hand involvement.

Mapping

Gurnett et al. (2010) described a 5-generation family with DA1 segregating as an autosomal dominant disorder with complete penetrance. Genomewide linkage data from 12 affected members revealed a multipoint maximum lod of 3.27 on chromosome 12q23.2. Recombinants delineated the critical region to an interval of 9 cM between SNPs rs3869308 and rs1196761.

Molecular Genetics

Gurnett et al. (2010) sequenced the MYBPC1 gene, which encodes the slow-twitch skeletal muscle myosin binding protein C1, in affected members of 2 families segregating autosomal dominant distal arthrogryposis and identified a different heterozygous missense mutation in each family (160794.0001-160794.0002) that segregated with disease. Neither mutation was found in chromosomes of 400 control individuals. Skeletal muscle biopsies from affected patients showed that type I (slow-twitch) fibers were smaller than type II fibers. Expression of a green fluorescent protein (GFP)-tagged MYBPC1 construct containing wildtype and DA1 mutations in mouse skeletal muscle revealed robust sarcomeric localization. In contrast, a more diffuse localization was seen when nonfused GFP and MYBPC1 proteins containing corresponding MYBPC3 (600958) amino acid substitutions (R326Q, E334K) that caused hypertrophic cardiomyopathy were expressed. These findings revealed that the MYBPC1 is a novel gene responsible for DA1B, although the mechanism of disease may differ from how some cardiac MYBPC3 mutations cause hypertrophic cardiomyopathy.