Mutations in the Sarcoglycan Genes in Patients with Myopathy

doi:10.1056/NEJM199702273360904

Volume 336:618-625		February 27, 1997		Number 9

Mutations in the Sarcoglycan Genes in Patients with Myopathy

David J. Duggan, B.S., J. Rafael Gorospe, M.D., Ph.D., Marina Fanin, M.S., Eric P. Hoffman, Ph.D., Corrado Angelini, M.D., E. Pegoraro, S. Noguchi, E. Ozawa, W. Pendlebury, A.J. Waclawik, D.A. Duenas, I. Hausmanowa-Petrusewicz, A. Fidzianska, S.C. Bean, J.S. Haller, J. Bodensteiner, C.M. Greco, A. Pestronk, A. Berardinelli, D.F. Gelinas, H. Abram, and R.W. Kuncl

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ABSTRACT

Background Some patients with autosomal recessive limb-girdlemuscular dystrophy have mutations in the genes coding for thesarcoglycan proteins ( ${alpha}$ -, ${beta}$ -, ${gamma}$ -, and ${delta}$ -sarcoglycan). To determinethe frequency of sarcoglycan-gene mutations and the relationbetween the clinical features and genotype, we studied severalhundred patients with myopathy.

Methods Antibody against ${alpha}$ -sarcoglycan was used to stain muscle-biopsyspecimens from 556 patients with myopathy and normal dystrophingenes (the gene frequently deleted in X-linked muscular dystrophy).Patients whose biopsy specimens showed a deficiency of ${alpha}$ -sarcoglycanon immunostaining were studied for mutations of the ${alpha}$ -, ${beta}$ -, and ${gamma}$ -sarcoglycan genes with reverse transcription of muscle RNA,analysis involving single-strand conformation polymorphisms,and sequencing.

Results Levels of ${alpha}$ -sarcoglycan were found to be decreased onimmunostaining of muscle-biopsy specimens from 54 of the 556patients (10 percent); in 25 of these patients no ${alpha}$ -sarcoglycanwas detected. Screening for sarcoglycan-gene mutations in 50of the 54 patients revealed mutations in 29 patients (58 percent):17 (34 percent) had mutations in the ${alpha}$ -sarcoglycan gene, 8 (16percent) in the ${beta}$ -sarcoglycan gene, and 4 (8 percent) in the ${gamma}$ -sarcoglycan gene. No mutations were found in 21 patients (42percent). The prevalence of sarcoglycan-gene mutations was highestamong patients with severe (Duchenne-like) muscular dystrophythat began in childhood (18 of 83 patients, or 22 percent);the prevalence among patients with proximal (limb-girdle) musculardystrophy with a later onset was 6 percent (11 of 180 patients).

Conclusions Defects in the genes coding for the sarcoglycanproteins are limited to patients with Duchenne-like and limb-girdlemuscular dystrophy with normal dystrophin and occur in 11 percentof such patients.

Source Information

From the Departments of Human Genetics, Molecular Genetics and Biochemistry, Pediatrics, and Neurology, University of Pittsburgh, Pittsburgh (D.J.D., J.R.G., E.P.H.); and the Regional Neuromuscular Center, Department of Neurology, University of Padua, Padua, Italy (M.F., C.A.).

Address reprint requests to Dr. Hoffman at Biomedical Science Tower W1211, Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.

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