The specific aims of this research proposal are to use microsatellite markers to more precisely map the gene responsible for Acrocephalosyndactyly III (ACS III) (Saethre-Chotzen syndrome), an autosomal dominant craniofacial disorder characterized by deformities of the organs of communication and hearing impairment, and to test for genetic heterogeneity among ACS III kindreds. Gene localization to a specific region of a chromosome leads to the eventual isolation of the gene. Thus gene mapping is a critical step toward the ultimate understanding of hearing impairment and ear development. Previous studies using DNAs from several small British families with ACS III produced significant LOD scores for restriction fragment length polymorphisms (RFLPs) and microsatellite markers in the 7p21 region at a recombination fraction (theta) of .05. In addition, a microsatellite mapping technique was used to refine the location of the gene to a 29 centiMorgan region between D7S513 and D7S516, with the tightest linkage to locus D7S493 (Z=5.04, theta=0.00). A large American family with ACS III has indicated their willingness to participate in a mapping study. A series of PCR-based microsatellite markers have been obtained and primers corresponding to these markers have been synthesized for chromosome 7p in the course of our mapping the gene for Crouzon syndrome. These microsatellite markers, plus newly released markers will be used to perform linkage analysis using the DNA of this large family with ACS III. The combination of these additional markers and a large family will narrow the region that ACS III maps to and confirm assignment of ACS III to 7p21. If linkage is not shown, this will be evidence that ACS III is a genetically heterogeneous disorder. Strategies to isolate the gene(s) or to perform DNA-based prenatal diagnoses will be very different if two genes cause the same phenotype. Genetic heterogeneity has been shown for other syndromes affecting the head and neck, including Usher Syndrome Type I and Type II and Pfeiffer syndrome. Syndromes associated with hearing impairment offer an excellent opportunity to isolate the genes responsible for ear development and hearing. The eventual isolation of the gene(s) for ACS III and the delineation of the protein products will help elucidate the biochemical and cytochemical mechanisms that control development of the human ear, face and cranium. Prenatal diagnosis and more accurate genetic counseling of affected individuals will be possible. This would be especially valuable for those patients with minimal expressivity and in those families where the gene may be a new mutation.
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