DESCRIPTION (Taken from the application): Limb-Girdle Muscular Dystrophy (LGMD) encompasses a clinically diverse group of disorders characterized by proximal muscle weakness first affecting the hip and shoulder girdle elevated creatinine kinase values, and non-specific changes in the muscle biopsy. In addition to clinical heterogeneity within the LGMD category, genetic heterogeneity is indicated by the existence of dominant and recessive forms. We have identified a large family with autosomal dominant LGMD and early onset Paget disease of bone (PDB). These individuals have bone pain in the hips, shoulders and back from the Paget disease. Individuals eventually become bed bound and die prematurely from progressive muscle weakness +/-cardiomyopathy in their forties to sixties. Laboratory investigation indicates elevated alkaline phosphatase levels in affected individuals. CPK is normal to mildly elevated. Muscle biopsy of the oldest affected male revealed non-specific changes and vacuolated fibers. Preliminary molecular analysis excluded linkage to the known loci for the autosomal dominant and recessive forms as well as 2 loci for autosomal dominant PDB and 6 loci for cardiomyopathy. Exclusion of the candidate loci prompted a genome-wide scan of 39 family members (9 affected, 24 unaffected, 6 spouses} with 402 polymorphic microsatellite markers (Marshfield Genotyping Services). The disease locus was linked to chromosome 9p21-q21 with marker D9S301 (max LOD=3.64), thus supporting our hypothesis that this family displays a genetically distinct form of Limb-Girdle-Muscular-Dystrophy associated with Paget disease of bone and cardiomyopathy. Subsequent haplotype analysis with a high density of microsatellite markers flanking D9S301 refined the disease locus to a 3.76 cM region on chromosome 9p21-13.2. This region excludes the IBM2 locus for autosomal recessive vacuolar myopathy. Two candidate genes mapped to the critical region, NDUFB6 and IL-11RA, are being examined for disease-associated mutations. NDUFB6 encodes a subunit of Complex I of the mitochondrial respiratory chain and the IL11RA gene product influences proliferation and differentiation of skeletogenic progenitor cells. Identification of the genes involved in the LGMDs has led to the elucidation of an entire family of proteins that function in the dystrophin-glycoprotein complex. and a basis for understanding the pathophysiology of this complex. Delineation of the genetic component responsible for the LGMD/PDB phenotype should promise similar insight and facilitate in the design of novel treatment protocols for the two disorders.