Mutations in the Sarcoglycan Genes in Patients with Myopathy

TLDR

Mutations in the sarcoglycan genes (α, β, γ, δ) underlie autosomal recessive limb‑girdle muscular dystrophy in a subset of patients. The study aimed to determine the frequency of sarcoglycan‑gene mutations and their relationship to clinical features and genotype in a large cohort of myopathy patients. The authors screened 556 myopathy patients with normal dystrophin genes by immunostaining for α‑sarcoglycan, then performed reverse transcription, single‑strand conformation polymorphism analysis, and sequencing on those with deficient staining. Among 54 patients with α‑sarcoglycan deficiency, 58 % carried sarcoglycan‑gene mutations (34 % α, 16 % β, 8 % γ), while 42 % had none; mutation prevalence was highest in Duchenne‑like childhood onset (22 %) and lower in later‑onset limb‑girdle (6 %), overall affecting 11 % of patients with normal dystrophin.

Abstract

Some patients with autosomal recessive limb-girdle muscular dystrophy have mutations in the genes coding for the sarcoglycan proteins (alpha-, beta-, gamma-, and delta-sarcoglycan). To determine the frequency of sarcoglycan-gene mutations and the relation between the clinical features and genotype, we studied several hundred patients with myopathy.Antibody against alpha-sarcoglycan was used to stain muscle-biopsy specimens from 556 patients with myopathy and normal dystrophin genes (the gene frequently deleted in X-linked muscular dystrophy). Patients whose biopsy specimens showed a deficiency of alpha-sarcoglycan on 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.Levels of alpha-sarcoglycan were found to be decreased on immunostaining of muscle-biopsy specimens from 54 of the 556 patients (10 percent); in 25 of these patients no alpha-sarcoglycan was detected. Screening for sarcoglycan-gene mutations in 50 of the 54 patients revealed mutations in 29 patients (58 percent): 17 (34 percent) had mutations in the alpha-sarcoglycan gene, 8 (16 percent) in the beta-sarcoglycan gene, and 4 (8 percent) in the gamma-sarcoglycan gene. No mutations were found in 21 patients (42 percent). The prevalence of sarcoglycan-gene mutations was highest among patients with severe (Duchenne-like) muscular dystrophy that began in childhood (18 of 83 patients, or 22 percent); the prevalence among patients with proximal (limb-girdle) muscular dystrophy with a later onset was 6 percent (11 of 180 patients).Defects in the genes coding for the sarcoglycan proteins are limited to patients with Duchenne-like and limb-girdle muscular dystrophy with normal dystrophin and occur in 11 percent of such patients.