Despite the remarkable advances in identifying mutations underlying human genetic disease, the predictive power of the genotype remains poor, in part because the ultimate clinical outcome in each patient is the net result of epistatic interactions between disease causing mutations and second site modifying alleles, as well as stochastic and environmental effects. Bardet-Biedl syndrome (BBS) represents a useful model to study epistasis;several studies have shown that modifying alleles in each of the twelve causative genes, as well as in other transcripts, modulate the penetrance and expressivity 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 its anchoring structure, the basal body, are required for the transmission morphogenetic cues and that failure of this process can be causally associated with some of the observed clinical phenotypes, such as renal cystic disease. Loss of function of several BBS proteins has been shown to disrupt non-canonical Wnt signaling, which in turn has been associated with some of the cystic phenotypes found in patients and vertebrate animal models. Focusing on the contribution of Wnt signaling to the renal phenotype, we reason that there will be proteins that have the ability to modulate the biochemical effect of loss of function mutations at one BBS locus by either exacerbating, ameliorating, or rescuing defective Wnt transmission. By definition, the transcripts that encode these molecules represent major candidates for contributing penetrance and expressivity modifying alleles in humans, the identification of which will: a) improve exponentially our understanding of genetic load in humans;b) facilitate the clinical management of the disorder;and c) be potentially relevant to the development of renal cystic disease in other ciliopathies. To explore these possibilities further, we propose to 1) investigate ~500 members of the newly defined ciliary proteome in modulating the Wnt signaling response in BBS mutant renal cells by utilizing a combination shRNAs, expression vectors, and luminescent reporters, and 2) explore the physiological relevance of these potential modifier proteins in modulating the renal phenotype of BBS patients by screening candidate genes for a haplotype signature that associates with disease phenotype and sequencing our BBS cohort for modifier alleles.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-F10-H (20))
Program Officer
Rankin, Tracy L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Davis, Erica E; Zhang, Qi; Liu, Qin et al. (2011) TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet 43:189-96
Merveille, Anne-Christine; Davis, Erica E; Becker-Heck, Anita et al. (2011) CCDC39 is required for assembly of inner dynein arms and the dynein regulatory complex and for normal ciliary motility in humans and dogs. Nat Genet 43:72-8
Kinzel, Doris; Boldt, Karsten; Davis, Erica E et al. (2010) Pitchfork regulates primary cilia disassembly and left-right asymmetry. Dev Cell 19:66-77
Valente, Enza Maria; Logan, Clare V; Mougou-Zerelli, Soumaya et al. (2010) Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes. Nat Genet 42:619-25
O'Toole, John F; Liu, Yangjian; Davis, Erica E et al. (2010) Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy. J Clin Invest 120:791-802
Harville, H M; Held, S; Diaz-Font, A et al. (2010) Identification of 11 novel mutations in eight BBS genes by high-resolution homozygosity mapping. J Med Genet 47:262-7
Khanna, Hemant; Davis, Erica E; Murga-Zamalloa, Carlos A et al. (2009) A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies. Nat Genet 41:739-45
Gerdes, Jantje M; Davis, Erica E; Katsanis, Nicholas (2009) The vertebrate primary cilium in development, homeostasis, and disease. Cell 137:32-45
Bialas, Nathan J; Inglis, Peter N; Li, Chunmei et al. (2009) Functional interactions between the ciliopathy-associated Meckel syndrome 1 (MKS1) protein and two novel MKS1-related (MKSR) proteins. J Cell Sci 122:611-24
de Pontual, Loïc; Zaghloul, Norann A; Thomas, Sophie et al. (2009) Epistasis between RET and BBS mutations modulates enteric innervation and causes syndromic Hirschsprung disease. Proc Natl Acad Sci U S A 106:13921-6

Showing the most recent 10 out of 11 publications