Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy


Miyoshi myopathy (MM) is an adult onset, recessive inherited distal muscular dystrophy that we have mapped to human chromosome 2p13. We recently constructed a 3-Mb P1-derived artificial chromosome (PAC) contig spanning the MM candidate region. This clarified the order of genetic markers across the MM locus, provided five new polymorphic markers within it and narrowed the locus to approximately 2 Mb. Five skeletal muscle expressed sequence tags (ESTs) map in this region. We report that one of these is located in a novel, full-length 6.9-kb muscle cDNA, and we designate the corresponding protein 'dysferlin'. We describe nine mutations in the dysferlin gene in nine families; five are predicted to prevent dysferlin expression. Identical mutations in the dysferlin gene can produce more than one myopathy phenotype (MM, limb girdle dystrophy, distal myopathy with anterior tibial onset).

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Figure 1: Overview of the MM locus and dysferlin cDNA.
Figure 2: Northern blot of five novel ESTs expressed in skeletal muscle.
Figure 3: Dysferlin amino acid sequence and hydrophobicity.
Figure 4: Representative pedigree with dysferlin mutations.

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The Cecil B. Day Investment Company and the Muscular Dystrophy Association funded many aspects of this project. R.B. is supported by NIH grants 5PO1AG12992, 5RO1N834913A and 5PO1NS31248. J.L. was funded by a post-doctoral fellowship of the Medical Research Council of Canada. M.A. received a stipend from the Muscular Dystrophy Association and the Pierre L de Bourgknecht Fund for ALS Research. P. de J. is supported by NIH (NIHGRI) grant 5RO1 HG1165 and U.S. Department of Energy grant DE-FCO3-96ER62294. E.S. is funded by the Canadian Genome Analysis and Technology Program. B.A.H. and K.J.B. were recipients respectively of NRSA fellowship IF32N10064 and a stipend from the Deater Foundation. I.I. and C.S. received grants from the Fondo Investigationes Sanitarias (F.I.S. 96/0863 and 98/5065 B.A.E.). C.A. is funded by grants from Telethon 916C and C19 and from a Finalized Research Grant 559/01/95 of Veneto Region. K.A. is supported by the Ministry of Health and Welfare (Japan) grants for the Center of Excellence and Brain Sciences. J.U. and M.F. are supported by the AFM, which funded family DNA collections in France; M.F. is also funded by Inserm (U153). We are grateful to L. Hayward for discussions of the predicted properties of dysferlin.

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Correspondence to Robert H. Brown Jr.

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