The goal of the research proposed here is to characterize the molecular defect responsible for split hand/split foot malformation, a human developmental disorder which results in abnormal hands and feet. Isolation of the SHSF gene will provide an opportunity to investigate the molecular basis of pattern formation in the human limb. In addition, the inheritance of SHSF exhibits a number of distinctive features, including reduced penetrance and variable expressivity, which will be amenable to molecular analysis upon cloning of the SHSF gene.
Our specific aims are to: 1. Employ positional cloning techniques to analyze the DNA of cytogenetically abnormal SHSF patients, and thereby isolate the SHSF gene. 2. Establish a repository of cell lines from individuals with SHSF and related malformations. This resource will facilitate cloning of the SHSF gene as well as future investigations of genotype-phenotype relationships in SHSF. Significant progress has already been made in attaining these goals. If the SHSF gene is cloned relatively early in the grant period, we will then: 3. Characterize mutations from SHSF patients to establish genotype-phenotype correlations. These studies will provide insight into the function of the SHSF gene product and will allow investigation of the disorder's unusual genetic properties on a molecular level. 4. Characterize the SHSF gene in patients who have other congenital anomalies in addition to SHSF. Such an analysis will clarify the relationship between these various syndromes and may allow investigation of the role that the SHSF gene product plays in aspects of human development other than limb formation. If such abnormalities are secondary to contiguous gene deletion syndromes, novel genes implicated in human development may be identified. 5. Isolate the mouse homolog of the human SHSF gene, and analyze a mouse mutant, Dactylaplasia, to determine whether it represents an animal model of SHSF. 6. Analyze SHSF pedigrees to determine whether this condition exhibits segregation distortion, and, if so, investigate the molecular basis of this unusual genetic phenomenon upon isolation of the gene. The proposed research offers a unique opportunity to isolate a gene which is responsible for a well characterized human limb malformation and promises to establish SHSF as a model system for the study of human limb development. Furthermore, isolation of the SHSF gene will eventually allow investigation of the molecular bases of reduced penetrance and variable expressivity, poorly understood genetic phenomena common to many inherited diseases. Finally, the relationship between SHSF and other birth defects will be resolved by characterization of the SHSF gene, allowing accurate genetic counseling to individuals with SHSF and related disorders.
