Nicholas Katsanis, Ph.D. (Baylor College of Medicine)
Professor, Dept. of Cell Biology
Director, Center for Human Disease Modeling
466 Nanaline Duke Building, Box 3709
Duke University Medical Center
Durham, NC 27710
Our laboratory uses a multidisciplinary approach to understand the genetic and cellular basis of pleiotropic disease. Our research is driven by several key, challenging questions, including:
• What is the genetic basis of phenotypic variability in seemingly monogenic disease?
• How is it that ubiquitously expressed genes give rise to specific phenotypes?
• What is the mechanistic defect of disorders that exhibit both structural and progressive features?
• Is there a functional link between rare disorders and common traits with overlapping clinical manifestations?
To address such questions, we focused on Bardet-Biedl syndrome, a genetically and clinically heterogeneous disease characterized by retinal dystrophy, polydactyly, obesity and a constellation of neurological and behavioral abnormalities (OMIM #209900).
We and others have shown that despite a historical dichotomy between monogenic and complex traits, there exists a continuum of genetic causality, whereby mutations at a discrete number of loci cooperate to either cause the disease or modify the onset and severity of the phenotype. In BBS, for example, we have shown that three alleles at two BBS loci can cooperate to influence the penetrance and/or the expressivity of the phenotype. We have been involved in the identification of five of the known eight BBS genes in the human genome and are working to a) identify additional loci; and b) dissect their genetic interaction. In addition, we are querying whether the BBS proteins are involved in common traits that overlap with the BBS phenotype, such as childhood asthma, obesity and psychiatric illness.
2. In vitro studies
To understand genetic interaction, we need to model it at the cellular level. To this end, we have identified a number of novel proteins that interact with the BBS proteins and are working to a) understand the nature of the BBS protein complexes; and b) determine the effect of mutations found in BBS patients on the function of such complexes. These studies are not only revealing new mechanistic insights but also helping identify new modifier genes for the BBS phenotypes.
3. In vivo studies
Together with a network of collaborators, we are recapitulating the human BBS genotypes in several model organisms, including mouse, C. elegans, Drosophila and C. reinhardtii. We are using these models to better understand the function of the BBS proteins as well as their genetic and physical interactions. We have shown recently that the BBS phenotype is caused by defects at the cilia of different cell types, and we are now investigating the cellular and biochemical properties of such structures and their importance in tissue physiology, with particular emphasis on neuronal determination, maturation and migration.
4. Global analysis of the ciliary proteome
To understand the function and dysfunction in our model, we need to assay the system in its totality. To that end, we have used a combination of computational genomics and bench biology to describe a large protein dataset involved in ciliary function and biogenesis. Our analyses suggest that we have identified most of the proteins required for the functionality of this organelle. We are now focusing on understanding the role of these proteins and their genetic and physical interactions by performing RNA interference coupled with microarray analysis on ciliated cells and observing the effects of loss of protein function on ciliary biology.
Riazuddin SA, Vasanth S, Katsanis N, Gottsch JD (2013) Mutations in AGBL1 Cause Dominant Late-Onset Fuchs Corneal Dystrophy and Alter Protein-Protein Interaction with TCF4. Am J Hum Genet. 93(4): 758-764
Nishiguchi KM, Tearle RG, Liu YP, Oh EC, Miyake N, Benaglio P, Harper S, Koskiniemi-Kuendig H, Venturini G, Sharon D, Koenekoop RK, Nakamura M, Kondo M, Ueno S, Yasuma TR, Beckmann JS, Ikegawa S, Matsumoto N, Terasaki H, Berson EL, Katsanis N, Rivolta C (2013) Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene. Proc Natl Acad Sci USA. 110(40): 16139-161-44
Seddon JM, Yu Y, Miller EC, Reynolds R, Tan PL, Gowrisankar S, Goldstein JI, Triebwasser M, Anderson HE, Zerbib J, Kavanagh D, Souied E, Katsanis N, Daly MJ, Atkinson JP, Raychaudhuri S (2013) Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nat Genet. Epub
Niederriter AR, Davis EE, Golzio C, Oh EC, Tsai IC, Katsanis N (2013) In Vivo Modeling of the Morbid Human Genome using Danio rerio. J Vis Exp (78)
Hjeij R, Lindstrand A, Francis R, Zariwala MA, Liu X, Li Y, Damerla R, Dougherty GW, Abouhamed M, Olbrich H, Loges NT, Pennekamp P, Davis EE, Carvalho CM, Pehlivan D, Werner C, Raidt J, Köhler G, Häffner K, Reyes-Mugica M, Lupski JR, Leigh MW, Rosenfeld M, Morgan LC, Knowles MR, Lo CW, Katsanis N, Omran H (2013) ARMC4 Mutations Cause Primary Ciliary Dyskinesia with Randomization of Left/Right Body Asymmetry. Am J Hum Genet. S0002-9297(13)00278-4
Wiszniewski W, Hunter JV, Hanchard NA, Willer JR, Shaw C, Tian Q, Illner A, Wang X, Cheung SW, Patel A, Campbell IM, Hixson P, Ester AR, Azamian MS, Potocki L, Zapata G, Hernandez PP, Ramocki MB, Santos-Cortez RL, Wang G, York MK, Justice MJ, Chu ZD, Bader PI, Omo-Griffith L, Madduri NS, Scharer G, Crawford HP, Yanatatsaneejit P, Eifert A, Kerr J, Bacino CA, Franklin AI, Goin-Kochel RP, Simpson G, Immken L, Haque ME, Stosic M, Williams MD, Morgan TM, Pruthi S, Omary R, Boyadjiev SA, Win KK, Thida A, Hurles M, Hibberd ML, Khor CC, Van Vinh Chau N, Gallagher TE, Mutirangura A, Stankiewicz P, Beaudet AL, Maletic-Savatic M, Rosenfeld JA, Shaffer LG, Davis EE, Belmont JW, Dunstan S, Simmons CP, Bonnen PE, Leal SM, Katsanis N, Lupski JR, Lalani SR (2013) TM4SF20 Ancestral Deletion and Susceptibility to a Pediatric Disorder of Early Language Delay and Cerebral White Matter Hyperintensities. Am J Hum Genet. S0002-9297(13)00269-3
Golzio C, Katsanis N (2013) Genetic architecture of reciprocal CNVs. Crr Opin Genet Dev. 23(3):240-8
Cardenas-Rodrigues M, Irgoin F, Osborn DP, Gascue C, Katsanis N, Beales PL, Badano JL (2013) The Bardet-Biedl Syndrome-related protein CCDC28B modulates mTORC2 function and interacts with SIN1 to control cilia length independently of the mTOR complex. Hum Mol Genet. 22(20):4031-42
van de Ven JP, Nilsson SC, Tan PL, Buitendijk GH, Ristau T, Mohlin FC, Nabuurs SB, Schoenmaker-Koller FE, Smailhodzic D, Campochiaro PA, Zack DJ, Duvvari MR, Bakker B, Paun CC, Boon CJ, Uitterlinden AG, Liakopoulos S, Klevering BJ, Fauser S, Daha MR, Katsanis N, Klaver CC, Blom AM, Hoyng CB, den Hollander AI (2013) A functional variant in the CFI gene confers a high risk of age-related macular degeneration. Nat Genet. 45(7):813-7
Katsanis SH, Katsanis N (2013) Molecular genetic testing and the future of clinical genomics. Nat Rev Genet. 14(6):415-26