Splicing mutation in dysferlin produces limb-girdle muscular dystrophy with inflammation

Mutations in dysferlin were recently described in patients with Miyoshi myo pathy, a disorder that preferentially affects the distal musculature, and i n patients with Limb-Girdle Muscular Dystrophy 2B, a disorder that affects the proximal musculature, Despite the phenotypic differences, the types of mutations associated with Miyoshi myopathy and Limb-Girdle Muscular Dystrop hy 2B do not differ significantly, Thus, the etiology of the phenotypic var iability associated with dysferlin mutations remains unknown. Using genetic linkage and mutation analysis, we identified a large inbred pedigree of Ye menite Jewish descent with limb-girdle muscular dystrophy, The phenotype in these patients included slowly progressive, proximal, and distal muscular weakness in the lower limbs with markedly elevated serum creatine kinase (C K) levels. These patients had normal development and muscle strength and fu nction in early life. Muscle biopsies from 4 affected patients showed a typ ical dystrophic pattern but interestingly, in 2, an inflammatory process wa s seen. The inflammatory infiltrates included primarily CD3 positive lympho cytes, Associated with this phenotype, we identified a previously undescrib ed frameshift mutation at nucleotide 5711 of dysferlin, This mutation produ ced an absence of normal dysferlin mRNA synthesis by affecting an acceptor site and cryptic splicing. Thus, splice site mutations that disrupt dysferl in may produce a phenotype associated with inflammation. (C) 2000 Wiley-Lis s, Inc.