The long term objective of this research program is to understand the phenotypic diversity of a complex mammalian locus, the mouse pink-eyed dilution locus. By definition, all mutant alleles of this locus affect pigmentation. However, several mutant alleles exhibit additional phenotypes, including sterility, cleft palate, and two distinct neurological disorders (jerky movement and tremors). All of the alleles with non-pigmentation phenotypes were derived by radiation-induced mutagenesis; preliminary studies indicate that these mutations result from deletions (or inversions). The pattern of overlap of these deletions, combined with complementation analysis of mutant alleles, imply that several (closely linked) genes are responsible for the diverse phenotypes of pink-eyed dilution mutants. Regions defining the genes associated with the phenotypes of sterility, neurological disorders and cleft palate have been localized. The three specific aims of this proposal are directed towards the isolation and characterization of these genes. They are: 1) To develop a comprehensive physical and genetic map of the pink-eyed dilution locus by molecular biological techniques (including pulsed-field gel electrophoresis) and by the analysis of compound mutants. 2) To determine the molecular basis of the neurological and fertility problems of specific mutant alleles by the methodical analysis of a region of ~30 kb associated with these phenotypes. 3) To determine the neuropathology and histopathology of a mutant allele associated with tremors and cleft palate, and to identify and isolate candidate genes associated with these phenotypes. This research has three major impacts on human health issues: 1) The human syntenic region of the pink-eyed dilution locus is associated with two genetic diseases, Prader-Willi Syndrome and Angelman Syndrome, with which it shares some of the same phenotypes. 2) A gene encoding a receptor subunit for GABA (an inhibitory neurotransmitter) is deleted in the mutant allele exhibiting tremors, providing a unique model for studying GABA system disorders, such as epilepsy. 3) The mutant allele associated with cleft palate offers an unparalleled model system to study the molecular basis of a recessive form of cleft palate. The identification of a gene associated with cleft palate (a common human birth defect) will represent a significant step in the efforts to understand the etiology of cleft palate.
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