MOLECULAR AND GENETIC ANALYSIS OF THE EEC SYNDROME

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DESCRIPTION (Adapted from investigator's Abstract): The ectodermal dysplasias consist of diseases with developmental abnormalities of ectodermal tissue primarily the hair, skin, teeth, and nails. Many forms of this disease present with other types of developmental disorders suggesting a common genomic alteration among them. One form, EEC, involves individuals who show evidence of ectodermal dysplasia, ectrodactyly and cleft palate. Previous work from this laboratory and others have mapped a form of ectrodactyly to human chromosome 7q21-22. Several families with EEC also show chromosomal abnormalities in this region. Thus, the Principal Investigator proposes that this area of the human genome contains the genes responsible for these developmental disorders. A YAC/cosmid/phage contig across this region of chromosome 7 has been developed and used to identify several candidate EEC genes. In this application, studies are proposed to further refine the EEC locus by a molecular analysis of the chromosome 7q21-22 target region in sporadic and familial EEC patients. To accomplish this aim, the investigator will look for submicroscopic deletions by PFGE and Southern analyses. At the same time, the technique of solution hybrid capture will be used to isolate candidate EEC genes from the target region. Patient material will then be screened for mutations and altered expression as well as look for mutations in these genes by SSCP analysis and loss of expression of one allele by polymorphic mRNA markers. Finally, patient samples will continue to be collected from sporadic and familial EEC patients to support these ongoing studies. This repository will be expanded to include other multiple phenotype disorders such as Rapp-Hodgkin and LADD which also include ED. It will then be determined if markers in the EEC critical region demonstrate linkage to these other types of ED-related families. These proposed studies offer a unique opportunity to isolate and characterize genes responsible for several well-characterized human developmental disorders. Furthermore, an understanding of the functions of these genes 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 determination of the relationship among the various birth defects associated with EEC will allow accurate genetic counseling to individuals with this disorder.