Calpain 3 gene mutations: genetic and clinico-pathologic findings in limb-girdle muscular dystrophy

Mutations in the calpain 3 gene have been proven to be responsible for limb -girdle muscular dystrophy (LGMD) type 2A. To determine the incidence and g enotypes of the calpain 3 (p94) gene mutations in Japanese LGMD patients, w e sequenced the gene in 80 patients with clinical characteristics of autoso mal recessive or sporadic LGMD. We identified 13 distinct pathogenic mutati ons in 21 patients (26%), including seven missense mutations, four splice-s ite mutations and two insertions in which six were novel mutations. Among t he 21 patients, 15 (71%) had three types of the common missense (G233V, R46 1C, D707G) and one insertion (1795-1796insA) mutation. The patients had slo wly progressive muscle weakness with age of onset of the disease varying fr om 6 to 52 years, averaging 20.9. The most striking pathologic findings wer e the presence of lobulated fibers in 14 patients, especially in the advanc ed stages. Differing from Duchenne and Becker muscular dystrophy, opaque (h ypercontracted) fibers were very rarely seen. These findings may be helpful in establishing diagnostic screening strategies in Japanese LGMD patients. (C) 2001 Elsevier Science B.V. All rights reserved.