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.