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From the Neuromuscular Center (Drs. Pegoraro and Angelini, M. Fanin), Department of Neurological and Psychiatric Sciences, University of Padova, Italy; and Cecil B. Day Laboratory for Neuromuscular Research (Drs. Matsuda-Asada and Brown), Massachusetts General Hospital, Charlestown, MA.
Address correspondence and reprint requests to M. Fanin, Department of Neurological and Psychiatric Sciences, University of Padova, via Giustiniani 5, 35128 Padova, Italy; e-mail: cmusc{at}ux1.unipd.it
BACKGROUND: Mutations in the genes encoding for calpain-3 and dysferlin are responsible for limb–girdle muscular dystrophy (LGMD) type 2A and 2B, the most common forms of autosomal recessive LGMD.
OBJECTIVE: To identify calpain-3 or dysferlin deficiency in a large cohort of patients with as yet unclassified LGMD and myopathy through candidate protein analysis.
METHODS: The authors’ muscle biopsy database search identified 407 candidate muscle biopsies with normal dystrophin and sarcoglycan. Calpain-3 and dysferlin were studied by Western blotting and immunohistochemistry.
RESULTS: Combined calpain-3 and dysferlin Western blot analysis identified calpain-3 deficiency in 66 (16%) muscle biopsies. In 31 cases (47%), the protein was absent, and in 35 (53%), it was severely reduced in amount (3 to 50% of control). Dysferlin deficiency was found in 26 (6.5%) muscle biopsies. In 9, the protein was absent (35%), and in 17 (65%), it was severely reduced in amount (traces to 20% of control). Twenty-eight percent (53/191) of patients with LGMD phenotype had calpain-3 deficiency. Sixty percent (21/35) of patients with distal myopathy had dysferlin deficiency. Dysferlin immunohistochemistry showed, in the completely dysferlin-deficient patients, absent reaction at the sarcolemma but positive nuclear membrane labeling and, in the partially dysferlin-deficient patients, scattered granular positive cytoplasmic areas and diffuse reaction in regenerating fibers.
CONCLUSION: About 25% of previously unclassified dystrophy/myopathy cases are due to calpain-3 or dysferlin protein deficiency. These results suggest that immunoblot analysis may be used to define patients for calpain-3 and dysferlin gene mutation studies.
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