CLINICAL AND MOLECULAR ANALYSIS OF A LARGE FAMILY WITH 3 DISTINCT PHENOTYPES OF PROGRESSIVE MUSCULAR-DYSTROPHY

We describe a unique six-generation, highly consanguineous family orig inating from an isolated mountainous village in the Russian province o f Daghestan. Three separate clinical phenotypes of progressive muscula r dystrophy were identified in this large family. Seven patients devel oped a classical limb-girdle variant of muscular dystrophy (LGMD), wit h disease onset at 15-30 years and loss of ambulation within a 25-year course. The second group included three patients with a slowly progre ssive distal myopathy first manifested in the late teens and confined to the tibial and calf muscles. Each of these two phenotypes segregate d independently as an autosomal recessive trait, and muscle biopsies s howed non-specific myopathic changes. Lastly, two male siblings exhibi ted an atypical variant of Duchenne muscular dystrophy confirmed by de tection of a deletion in the dystrophin gene. To clarify the molecular basis of the polymorphic autosomal recessive form of muscular dystrop hy in this kindred, we performed molecular genetic studies on 67 famil y members and obtained significant evidence for linkage to chromosome 2p. A maximum pairwise lod (logarithm of odds) score of 5.64 was achie ved at the Zero recombination fraction (i.e. at theta = 0.00) for locu s D2S291; multipoint linkage analysis confirmed the most likely locati on of a mutant gene near D2S291. The patients with LGMD and those with the distal muscular dystrophy phenotype share a common affected homoz ygous haplotype associated with the same founder chromosome; key recom binants defined D2S286 and D2S292 to be the closest loci flanking the mutant gene. Remarkably, two clinically distinct forms of autosomal re cessive muscular dystrophy, LGMD type 2B (LGMD2B) and Miyoshi myopathy , were recently mapped to the same locus. We suggest that all three ch romosome 2p-linked conditions may represent allelic disorders, i.e. di fferent phenotypic expressions of a single gene.