Pathology

Novel K7del mutation in TPM2 causes distal arthrogryposis type 7 (trismus-pseudocamptodactyly).

A novel, single amino acid deletion (K7del) near the N-terminus of tropomyosin 2 (β-tropomyosin) is the second genetic cause discovered for distal arthrogryposis type 7 (DA7). The collaboration of an international group of physicians and scientists led to the publication of this observation in the February 2013 issue of Brain. Previously, all DA7 patients were thought to have mutations in the myosin heavy chain gene, MYH8. The DA7 clinical phenotype is characterized by trismus and pseudocamptodactyly. The observation of nemaline rods and minicores (core-rod myopathy) in the muscle biopsies of autosomal dominant families led to the discovery of the K7del TPM2 mutation using a range of techniques including linkage analysis, Sanger sequencing, and exome sequencing by several groups in the United States and Europe. Dr. Steven Moore at The University of Iowa coordinated efforts to characterize two families within the USA. He and Dr. Tom Winder at PreventionGenetics worked with collaborators in the UK to characterize two additional families. Joel Carl helped extensively with the manuscript figures. Dr. James Dowling at the University of Michigan expressed the mutant TPM2 in zebrafish where it failed to localize properly in sarcomeric thin filaments and altered sarcomere length during development. His team at Michigan also performed computational analysis in modeling experiments that suggest the K7del mutation interrupts head-to-tail polymerization of β-tropomyosin dimmers.

 This work expands the clinical, histopathological, and genetic spectrum of TPM2-related myopathies. Previously reported TPM2 mutations had been associated with nemaline myopathy, cap myopathy, Escobar syndrome and distal arthrogryposis types 1A and 2B.

The entire article.

PubMed