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A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B

Abstract

The limb-girdle muscular dystrophies are a genetically heterogeneous group of inherited progressive muscle disorders that affect mainly the proximal musculature, with evidence for at least three autosomal dominant and eight autosomal recessive loci. The latter mostly involve mutations in genes encoding components of the dystrophin-associated complex; another form is caused by mutations in the gene for the muscle-specific protease calpain 3. Using a positional cloning approach, we have identified the gene for a form of limb-girdle muscular dystrophy that we previously mapped to chromosome 2p13 (LGMD2B ). This gene shows no homology to any known mammalian gene, but its predicted product is related to the C. elegans spermatogenesis factor fer-1. We have identified two homozygous frameshift mutations in this gene, resulting in muscular dystrophy of either proximal or distal onset in nine families. The proposed name `dysferlin' combines the role of the gene in producing muscular dystrophy with its C. elegans homology.

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Figure 1: Pedigree and haplotype data for the LGMD2B family LG-21.
Figure 2: Representation of YAC and PAC clones in the LGMD2B critical region (Y, YAC; P, PAC).
Figure 3: Expression analysis of a candidate LGMD2B gene.
Figure 4: The predicted partial amino acid sequence encoded by the dysferlin gene.
Figure 5: Mutations in LGMD2B families.

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Acknowledgements

We are grateful to all clinicians who contributed families not reported here and to participating patients. We have enjoyed the many discussions with R. Brown and his group in Boston in the course of this work. L. Anderson studied the muscle samples with antibodies to caveolin and calpain 3. HGMP provided library facilities, IMAGE clones and use of computing facilities. R. Parevi provided the control Moroccan samples. O. Williams provided technical assistance with sequencing in Newcastle, and C. Beley and C. Calloustian provided technical assistance with sequencing at Genethon. Grants for our work have been awarded by the Muscular Dystrophy Group of Great Britain, the Medical Research Council of Great Britain, the Italian Telethon, (Newcastle upon Tyne) the Association Francais contre les Myopathies, (Paris) FAPEP, CNPq, PRONEX, FINEP and ABBIM (Sao Paulo).

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Correspondence to Kate Bushby.

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Bashir, R., Britton, S., Strachan, T. et al. A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nat Genet 20, 37–42 (1998). https://doi.org/10.1038/1689

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