The goal of this project is to identify genes that contain mutations causing EB. Genes or chromosomal loci that are the site of EB mutations will be found by genetic linkage to EB in families. A second goal of the project is to determine the extent of heterogeneity in the underlying gene defects within the clinical subtypes of EB.
The specific aims of this project are: 1. To identify families with EB, and to collect samples for analysis of DNA of family members for linkage studies. 2. To map the gene locus responsible for the EB defect in each of the families by genetic linkage to a DNA polymorphism in a candidate gene or a mapped chromosomal locus. a. Dystrophic EB (EBD). For both dominant and recessive forms, the leading candidate gene to be tested is the type VII procollagen gene (COL7A1). b. EB simplex (EBS). The loci to be tested are genes or loci where other EB mutations have been mapped: 1) Keratin genes (KRT), located on chromosomes 12q and 17q, or nearby chromosomal markers. 2) chromosome lq (near AT3), the site of the EBS2 mutation in an Irish EBS (Koebner) family. 3) chromosome 8q24 (near GPT), the site of the EBS1 (Ogna) mutation in a Norwegian family. 3. To accomplish the objectives of specific aim 2, it will be necessary to develop efficient assays and more informative markers for each of the candidate genes or chromosomal loci to be tested. Additional RFLPs and polymorphic short tandem repeats will be identified at these loci. 4. To determine the extent of genetic heterogeneity of the phenotypic subtypes of EB, by determining how many families have mutations associated with each mapped EB locus, and how many remain undefined. 5. In the event that a class of EB families has a gene defect that is not mapped, the map location of the mutant gene will be determined by linkage analysis with additional candidate genes of the basement membrane zone and with a battery of chromosomal genetic markers.
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