Identical mutation in patients with limb girdle muscular dystrophy type 2Bor Miyoshi myopathy suggests a role for modifier gene(s)

Limb girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM), a distal muscular dystrophy, are both caused by mutations in the recently c loned gene dysferlin, gene symbol DYSF. Two large pedigrees have been descr ibed which have both types of patient in the same families. Moreover, in bo th pedigrees LGMD2B and MM patients are homozygous for haplotypes of the cr itical region, This suggested that the same mutation in the same gene would lead to both LGMD2B or MM in these families and that additional factors we re needed to explain the development of the different clinical phenotypes. In the present paper we show that in one of these families Pro791 of dysfer lin is changed to an Arg residue. Both the LGMD2B and MM patients in this k indred are homozygous for this mutation, as are four additional patients fr om two previously unpublished families. Haplotype analyses suggest a common origin of the mutation in all the patients. On western blots of muscle, LG MD2B and MM patients show a similar abundance in dysferlin staining of 15 a nd 11%, respectively. Normal tissue sections show that dysferlin localizes to the sarcolemma while tissue sections from MM and LGMD patients show mini mal staining which is indistinguishable between the two types. These findin gs emphasize the role for the dysferlin gene as being responsible for both LGMD2B and MM, but that the distinction between these two clinical phenotyp es requires the identification of additional factor(s), such as modifier ge ne(s).