Oligogenic disorders are an expanding category of genetic diseases in which mutations at a limited number of loci are responsible either for the pathogenesis or the modulation of a phenotype. Just as studies on the molecular mechanisms of monogenic diseases improved our understanding of basic cellular processes, deciphering the underlying molecular basis of more complex inheritance patterns will facilitate the generation of statistical and molecular tools for the dissemination of multifactorial traits. This proposal focuses on Bardet-Biedl syndrome (BBS), a useful model of oligogenic inheritance. BBS is a genetically heterogeneous, pleiotropic disease characterized primarily by retinal dystrophy, obesity, polydactyly, hypogenitalism, renal malformations and developmental delay. Historically, BBS has been considered an autosomal recessive disorder and based on this model six loci have been mapped. However, the identification of the first two BBS genes (BBS2 and BBS6) has indicated that BBS may deviate from classical Mendelian genetics, as recent data suggest that three mutations at two loci may be required for pathogenesis. We propose to investigate the molecular pathogenesis of BBS and to perform genetic and functional evaluations of this """"""""triallelic"""""""" model of inheritance. We will recruit additional BBS families and investigate the relationship between BBS2 and BBS6 further, as well as query whether the recently cloned BBS4 locus also exhibits triallelic inheritance. We will also investigate the cellular basis of the synergistic action of the mutant BBS genotypes by performing yeast two-hybrid and co-immunoprecipitation studies. These experiments will test for interactions between the BBS proteins, as well as identify other members of the BBS pathway(s), which may prove important in expanding our understanding of the molecular mechanism of this disorder. Finally, we propose to recapitulate the human genotype and phenotype in the mouse by ablating Bbs6 and Bbs2 and crossing them to create animals homozygous null at one locus and heterozygous null at the second locus. We will thus test whether three null mutant alleles are necessary and sufficient for pathogenesis, dissect the phenotype at the cellular level, and obtain important tools for the formation and testing of subsequent hypotheses. Completion of our specific aims is likely to advance substantially our understanding of the cellular basis of triallelism, which has the potential to serve as a powerful model that bridges classical genetics and complex traits. ? ?
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