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Calpain III mutation analysis of a heterogeneous limb–girdle muscular dystrophy population

From the Department of Molecular Genetics and Biochemistry (F.-L. Chou and Dr. Hoffman), University of Pittsburgh, PA; the Department of Clinical Neurology (Dr. Angelini), University of Padova, Italy; Shriners Hospital for Children of Northern California (Dr. Daentl), Sacramento, CA; the Department of Neurology (Dr. Garcia), Louisiana State University Medical Center, New Orleans, LA; the Department of Pathology (Dr. Greco), California Pacific Medical Center, San Francisco, CA; the Neuromuscular Unit (Drs. Hausmanowa–Petrusewicz and Fidzianska), Medical Research Center, Polish Academy of Science, Warsaw, Poland; and the Department of Pediatrics (Drs. Wessel and Hoffman), University of Pittsburgh School of Medicine, PA.

Address correspondence and reprint requests to Dr. Eric P. Hoffman, W1211 Biomedical Science Tower, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; e-mail: eric{at}hoffman.mgen.pitt.edu

OBJECTIVE: To determine the frequency of calpain III mutations in a heterogeneous limb–girdle muscular dystrophy (LGMD) population.

BACKGROUND: Mutations of the calpain III gene have been shown to cause a subset of autosomal recessive LGMDs. Patient populations studied to date have been primarily of French and Spanish origin, in which calpain III may cause 30% of autosomal recessive MDs. The incidence of calpain III mutations in non–French/Spanish MD patients has not been studied thoroughly. No sensitive and specific biopsy screening methods for detecting patients with abnormal calpain III protein are available. Thus, detection of patients relies on direct detection of gene mutations.

METHODS: The authors studied the calpain III gene in 107 MD patient muscle biopsies exhibiting normal dystrophin. Muscle biopsy RNA was produced for each patient, and the entire calpain III complementary DNA was screened for mutations by reverse-transcriptase PCR/single-strand conformation polymorphism using three different conditions.

RESULTS: The authors identified nine patients (eight unrelated) with causative mutations. Six of the seven distinct mutations identified are novel mutations and have not been described previously.

CONCLUSION: The results suggest that approximately 9.2% of patients in the heterogeneous population with an LGMD diagnosis will show mutations of the calpain III gene. Interestingly, two patients were heterozygous for a single mutation at the DNA level, whereas only the mutant allele was observed at the RNA level. This suggests that there are undetectable, nondeletion mutations that ablate expression of the calpain III gene.

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