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

From the Day Neuromuscular Research Laboratory (Drs. Aoki, Liu, and R.H. Brown, Jr., and J. Oeltjen, H.E.V. Brown, and D. McKenna-Yasek), Massachusetts General Hospital East, Charlestown; Department of Neurology (Dr. Aoki), Tohoku University School of Medicine, Sendai, Japan; Phage Tech (Dr. Liu), Montreal, Quebec, Canada; Genethon (Drs. Richard, Britton, Marchand, Bourg, and Beley), URA CNRS 1922 Every, France; Department of Biological Sciences (Dr. Bashir), Durham University, Durham, UK; Department of Biochemistry and Genetics (S.M. Keers and Dr. Bushby), University of Newcastle, Newcastle-upon-Tyne, UK; Department of Neuromuscular Research (Dr. Arahata), National Institute of Neuroscience, National Center for Neurology and Psychiatry, Tokyo, Japan; Department of Neurology (Drs. Bohlega and Cupler), King Faisal Hospital, Saudi Arabia; Neurology Department (Dr. Illa), Hospital Sta Creu i Sant Pau, Barcelona, Spain; Department of Neurology (Dr. Majneh), Oulu University, Finland; Department of Neurology (Dr. Barohn), University of Texas, Southwestern Medical Center at Dallas, TX; Institut de Myologie (Drs. Urtizberea and Fardeau), Association Francaise Contre les Myopathies, Hopital de la Salpetriere, Paris, France; Department of Neurology (Dr. Amato), Brigham and Women’s Hospital, Boston, MA; Department of Biology (Dr. Angelini), University of Padua, Italy; and Weizman Institute (Dr. Beckmann), Rehovot, Israel.

Address correspondence and reprint requests to Dr. R.H. Brown, Jr., Massachusetts General Hospital, MGH-East, Room 3125, Building 114, 16th Street, Navy Yard, Charlestown, MA 02129; e-mail: brown{at}helix.mgh.harvard.edu

OBJECTIVE: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

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