Despite remarkable advances in the identification of genetic and genomic lesions associated with human genetic disease, the predictive power of the genotype remains coarse, in part because the clinical outcome in each patient is the net result of epistatic interactions, as well as stochastic and environmental effects. The dissection of epistasis can be challenging, since the magnitude of effect of epistatic alleles can be modest, a problem confounded further by locus and allelic heterogeneity. Bardet-Biedl syndrome (BBS) represents a useful model to study epistasis. Although transmitted primarily as an autosomal recessive trait, several studies have shown that modifying alleles modulate the penetrance and severity of the disorder. BBS also represents a model ciliopathy, an emerging group of clinically distinct but phenotypically overlapping disorders that include polycystic kidney disease (PKD), Nephronophthisis (NPHP), Joubert syndrome (JS) and Meckel-Gruber syndrome (MKS). Recent data have shown that the cilium, and it anchoring structure, the basal body, are required for the interpretation of morphogenetic signals such as Wnt and Shh and that failure of this process can be causally associated with several of the clinical phenotypes pathognomonic of these syndromes. In this proposal we wish to capitalize on the improved understanding of the biochemical basis of ciliopathies to improve our understanding of epistasis, to expand the predictive power of the genotype, and to develop models and concepts that will facilitate the dissection of both Mendelian and complex traits. We will first combine data from the recently-described ciliary proteome with genetic information from BBS and MKS patients to both identify new genes causally associated with these disorders and to clone loci that contribute potential penetrance and severity modifiers. Second, we will develop in vivo phenotyping assays in zebrafish embryos and implement those to assess the pathogenic potential of oligogenic variants and to ask how do the properties of this population of alleles might differ from alleles sufficient to cause recessive disease. Finally, taking advantage of recent discoveries that suggest that cilia and basal bodies regulate Wnt signaling, we will interrogate the ciliary proteome to identify new proteins whose overexpression or suppression can ameliorate or exacerbate the cellular Wnt defect established by loss of BBS function;genes encoding these proteins will be natural candidates for bearing modifier alleles in humans. These studies will to provide new mechanistic insights on second-site modification as a major source of variability in the expressivity of human phenotypes and will likely provide models that will inform the study of both Mendelian and complex traits.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Oster-Granite, Mary Lou
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Duke University
Anatomy/Cell Biology
Schools of Medicine
United States
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