ClinVar Genomic variation as it relates to human health

In 8 patients from 5 unrelated families with congenital myopathy-23 (CMYO23; 609285), Mokbel et al. (2013) identified a heterozygous 3-bp deletion (c.19_21delAAG) in exon 1 of the TPM2 gene, resulting in the deletion of residue lys7 (K7del), which is 1 of 3 highly conserved lysine residues at the N terminus. The transmission pattern in 2 families was consistent with autosomal dominant inheritance; the mutation was suspected to have occurred de novo in 3 other families. The mutation was not found in the Exome Variant Server database. Studies of patient muscle and differentiated myotubes transfected with the mutation suggested that the mutant protein incorporates poorly into sarcomeres and likely accumulates in nemaline bodies, and interferes with wildtype protein in a dominant-negative manner. Patient myofibers had normal force generation, but increased sensitivity to calcium in motility assays. The mutant protein also showed reduced binding affinity for actin and a decreased ability to polymerize into long tropomyosin filaments. Mokbel et al. (2013) noted that the presence of joint contractures was the most prominent clinical feature in these patients and that 1 patient had hypertonicity. These findings suggested that the joint contractures may result from impaired muscle relaxation and a tendency for muscles to slowly shorten. Progressive muscle weakness in adulthood may result from a combination of muscle degeneration and apoptosis due to cellular stress. Davidson et al. (2013) identified a heterozygous K7del mutation, which they stated resulted from c.20_22del, in affected members of 4 families with a phenotype consistent with nemaline myopathy. Common clinical features in the families included muscle weakness and the presence of early distal extremity contractures combined with trismus. These findings unified the phenotype of congenital myopathy with distal arthrogryposis (DA1A; 108120). The mutation in 1 family was found by whole-exome sequencing and confirmed by Sanger sequencing. It segregated with the disorder and was not found in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, or in an in-house exome database. The mutation in the other families was found by candidate gene testing. Molecular modeling predicted that the mutation would alter protein-protein binding between TPM2 and other proteins as well as disturb the head-to-tail polymerization of TPM2 dimers. Expression of the mutation in developing zebrafish showed that the mutant protein did not localize properly within the thin filament compartment and altered sarcomere length, suggesting that it impaired sarcomeric structure. Areas of perimembranous accumulations of alpha-actinin were observed in mutant myofibers, consistent with findings in nemaline myopathy. (less)