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).

[1]  S. Ward,et al.  A nematode gene required for sperm vesicle fusion. , 1997, Journal of cell science.

[2]  E. Hoffman,et al.  Clinical and Histopathological Features of Abnormalities of the Dystrophin‐Based Membrane Cytoskeleton , 1996, Brain pathology.

[3]  S. Ward,et al.  Sperm morphogenesis in wild-type and fertilization-defective mutants of Caenorhabditis elegans , 1981, The Journal of cell biology.

[4]  K. Campbell,et al.  Dystroglycan: an extracellular matrix receptor linked to the cytoskeleton. , 1996, Current opinion in cell biology.

[5]  H. Kawai,et al.  Autosomal recessive distal muscular dystrophy as a new type of progressive muscular dystrophy. Seventeen cases in eight families including an autopsied case. , 1986, Brain : a journal of neurology.

[6]  L. Kunkel,et al.  Beyond dystrophin: current progress in the muscular dystrophies. , 1996, Current opinion in pediatrics.

[7]  M. Passos-Bueno,et al.  Confirmation of the 2p locus for the mild autosomal recessive limb-girdle muscular dystrophy gene (LGMD2B) in three families allows refinement of the candidate region. , 1995, Genomics.

[8]  S. Tsuji,et al.  Refined genetic location of the chromosome 2p-linked progressive muscular dystrophy gene. , 1997, Genomics.

[9]  L Kruglyak,et al.  An STS-Based Map of the Human Genome , 1995, Science.

[10]  K. Campbell,et al.  Muscular dystrophies and the dystrophin-glycoprotein complex. , 1997, Current opinion in neurology.

[11]  R. H. Brown,et al.  Dystrophin-associated proteins and the muscular dystrophies. , 1997, Annual review of medicine.

[12]  J. Weissenbach,et al.  Genetic and physical mapping at the limb-girdle muscular dystrophy locus (LGMD2B) on chromosome 2p. , 1996, Genomics.

[13]  P. Deloukas,et al.  A Gene Map of the Human Genome , 1996, Science.

[14]  T. Südhof,et al.  C 2-domains , Structure and Function of a Universal Ca 2 1-binding Domain * , 1998 .

[15]  V. Beneš,et al.  Direct primer walking on P1 plasmid DNA. , 1997, BioTechniques.

[16]  T. Hudson,et al.  Isolation and chromosomal assignment of 100 highly informative human simple sequence repeat polymorphisms. , 1992, Genomics.

[17]  J. Haines,et al.  Linkage of Miyoshi myopathy (distal autosomal recessive muscular dystrophy) locus to chromosome 2p12-14 , 1995, Neurology.

[18]  L. Peltonen,et al.  Assignment of the tibial muscular dystrophy locus to chromosome 2q31. , 1998, American journal of human genetics.

[19]  T. Sasaki,et al.  Doc2: a novel brain protein having two repeated C2-like domains. , 1995, Biochemical and biophysical research communications.

[20]  M. Kozak.  The scanning model for translation: an update , 1989, The Journal of cell biology.

[21]  Y. Takai,et al.  Molecular cloning of an isoform of Doc2 having two C2-like domains. , 1995, Biochemical and biophysical research communications.

[22]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[23]  J. Weber,et al.  Survey of trinucleotide repeats in the human genome: assessment of their utility as genetic markers. , 1995, Human molecular genetics.

[24]  Y. Nishizuka,et al.  The molecular heterogeneity of protein kinase C and its implications for cellular regulation , 1988, Nature.

[25]  D. Le Paslier,et al.  Genetic fine mapping of the Miyoshi myopathy locus and exclusion of eight candidate genes , 1998, Neurogenetics.

[26]  C. Greenberg,et al.  Limb-girdle muscular dystrophy and Miyoshi myopathy in an aboriginal Canadian kindred map to LGMD2B and segregate with the same haplotype. , 1996, American journal of human genetics.

[27]  Isabelle Richard,et al.  Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A , 1995, Cell.

[28]  E. Hoffman,et al.  Mutations in the integrin α7 gene cause congenital myopathy , 1998, Nature Genetics.

[29]  K. Johnson.  An Update. , 1984, Journal of food protection.

[30]  S. Dimauro,et al.  Mitochondrial DNA Mutations and Pathogenesis , 1997, Journal of bioenergetics and biomembranes.

[31]  Josep Rizo,et al.  Synaptotagmins: C2-Domain Proteins That Regulate Membrane Traffic , 1996, Neuron.

[32]  S. Ward,et al.  Caenorhabditis elegans fertilization-defective mutants with abnormal sperm. , 1980, Genetics.

[33]  K. Bushby,et al.  A gene for autosomal recessive limb-girdle muscular dystrophy maps to chromosome 2p. , 1994, Human molecular genetics.

[34]  H. Horvitz,et al.  Mutations in the glutamate transporter EAAT2 gene do not cause abnormal EAAT2 transcripts in amyotrophic lateral sclerosis , 1998, Annals of neurology.

[35]  P. D. de Jong,et al.  Generation of a 3-Mb PAC contig spanning the Miyoshi myopathy/limb-girdle muscular dystrophy (MM/LGMD2B) locus on chromosome 2p13. , 1998, Genomics.

[36]  M. Kozak.  An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs. , 1987, Nucleic acids research.