Human genetics research in this laboratory falls within three general categories. The first involves the chromosomal localization of cloned sequences including genes and tumor breakpoints by Southern analysis of human-rodent somatic cell hybrids, in situ hybridization, and genetic linkage analysis in 40 large CEPH families. About 20 additional cloned genes have been mapped during the past year by one or more of these methods. Of special note are localization of the Vasopressin V2 receptor to Xq27-q28 in the same region as the nephrogenic diabetes insipidus (NDI) locus and mapping of a plasma membrane Ca ATPase (PMCA2) to the 3p25-p26 boundary which contain the locus for von Hippel Lindau syndrome (VHL). The second involves the use of linkage analysis for mapping and identifying specific tumor susceptibility, and other disease, genes in affected families. Collaboration with Drs. D. Parry and R. Eldridge continues in mapping the neurofibromatosis 2 (NF2) gene, and two new microsatellite markers near this locus were used to localize points of recombination near the NF2 gene in individuals from two families. Genes responsible for several genetic skin diseases are being mapped in collaboration with Drs. P. Steinert and S.J. Bale. Epideromolytic hyperkeratosis (EHK) was found to cosegregate with the type II keratin gene cluster on chromosome 12q and probably involves the keratin 1 gene. Studies are in progress with Epidermolysis vulgaris, Darier's disease, and Basal nevus syndrome. The third area involves cloning and sequencing regions on chromosomes 12 and 22 containing polymorphic long repeats of trinucleotides to use in constructing high resolution genetic and physical maps of these chromosomes for mapping NF2 and other disease genes. Oligonucleotide primers are synthesized to permit PCR amplification of genomic DNAs. Most tracts have been found to be multiallelic and highly polymorphic, and some were used for linkage analysis in CEPH and NF2 families. Most of the (AAT)n tracts immediately flank the 3' end of ALU sequences (i.e. in poly A flanks) but this has not precluded use of these tracts.
