Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy

TLDR

Mutations in the skeletal muscle gene dysferlin cause the autosomal recessive muscular dystrophies Miyoshi myopathy and limb girdle muscular dystrophy type 2B, and understanding its genomic organization aids mutation detection and functional studies. The study aimed to map the dysferlin gene’s genomic structure, screen for mutations, and survey clinical features in 21 patients with confirmed dysferlin defects. Genomic organization was determined by comparing dysferlin cDNA with PAC‑derived genomic sequences, while mutational screening used conformational analysis and sequencing of genomic DNA and cDNA, and patient clinical records were retrospectively reviewed. The dysferlin gene contains 55 exons spanning >150 kb, nine novel MM‑associated mutations were identified, and patients had a narrow onset range with a mean age of 19.0 ± 3.9 years, confirming dysferlin mutations in MM and LGMD2B and refining disease onset timing.

Abstract

<b><i>Objective:</i></b> Mutations in the skeletal muscle gene dysferlin cause two autosomal recessive forms of muscular dystrophy: Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B). The purpose of this study was to define the genomic organization of the dysferlin gene and conduct mutational screening and a survey of clinical features in 21 patients with defined molecular defects in the dysferlin gene. <b><i>Methods:</i></b> Genomic organization of the gene was determined by comparing the dysferlin cDNA and genomic sequence in P1-derived artificial chromosomes (PACs) containing the gene. Mutational screening entailed conformational analysis and sequencing of genomic DNA and cDNA. Clinical records of patients with defined dysferlin gene defects were reviewed retrospectively. <b><i>Results:</i></b> The dysferlin gene encompasses 55 exons spanning over 150 kb of genomic DNA. Mutational screening revealed nine novel mutations associated with MM. The range of onset in this patient group was narrow with a mean of 19.0 ± 3.9 years. <b><i>Conclusion:</i></b> This study confirms that the dysferlin gene is mutated in MM and LGMD2B and extends understanding of the timing of onset of the disease. Knowledge of the genomic organization of the gene will facilitate mutation detection and investigations of the molecular biologic properties of the dysferlin gene.