The goal of this project is to identify the gene which is abnormal in facioscapulohumeral dystrophy (FSHD). FSHD is an autosomal dominant muscular dystrophy which is recognized clinically by its preferential involvement of the facial muscles and scapular fixators. The etiology is unknown and there is no specific treatment. The FSHD locus has been mapped to 4q35 (Wijmenga et al. 1990), however the linkage map is incomplete and no distal flanking marker has been identified. We will identify the FSHD gene using several established approaches. First, we will further localize FSHD in a high resolution map of 4q35. Linkage mapping of all new markers in FSHD and normal families will place FSHD in the genetic map. Pulsed field gel electrophoresis, somatic cell hybrids and yeast artificial chromosomes will be used in physical mapping of 4q35 markers. New markers will be identified through a collaborative effort to clone the 4q telomere which must either flank or contain the FSHD gene, followed by a cosmid walking strategy. The focus will be on developing and using high heterozygosity, sequence based polymorphisms~ such as the microsatellite repeats. Second, we will define a mouse chromosome segment which is homologous to 4q35 through use of interspecific backcrossed mice. In situ hybridization of the marker KLK3 suggested this region of homology may be found on mouse chromosome 8 (Beaubein et al. 1991). We have confirmed this result by showing linkage between Fll and UCP in the backcrossed mice. The mouse map will suggest new markers for mapping FSHD or new candidate genes, and has identified a possible animal model for FSHD. Third, we will identify and characterize candidate genes for FSHD. Resources available to use for identifying candidate genes include an investigation of dystrophin associated proteins in FSHD, a possible animal model (myd mouse) and homologous recombination vectors for use in screening a muscle cDNA library. Characterization of candidate genes will include genetic and physical mapping, hybridization with Northern blots, demonstration of conservation on zoo blots, sequence analysis, then a search for mutations in FSHD patients. The long term goal of this work is to identify the gene product and understand its role in producing this muscle disease.