| Associate Professor Departments of Ophthalmology, Molecular Biology and Genetics |  |
Education:
B.S., University College London, 1993
Ph.D., University of London, 1997
Postdoc, Baylor College of Medicine, 2000
Main Interests:
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).
1. Genetics
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.
Selected Publications
Katsanis N, Beales PL, Woods MO, Lewis RA, Green JS, Parfrey PS, Ansley SJ,Davidson WS, Lupski JR. Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome. Nat Genet. 2000 Sep;26(1):67-70.
Katsanis N, Ansley SJ, Badano JL, Eichers ER, Lewis RA, Hoskins BE,Scambler PJ, Davidson WS, Beales PL, Lupski JR. Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder. Science. 2001 Sep 21;293(5538):2256-9.
Badano JL, Katsanis N. Beyond Mendel: an evolving view of human genetic disease transmission. Nat Rev Genet. 2002 Oct;3(10):779-89.
Badano JL, Ansley SJ, Leitch CC, Lewis RA, Lupski JR, Katsanis N. Identification of a novel Bardet-Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2. Am J Hum Genet. 2003 Mar;72(3):650-8.
Beales PL, Badano JL, Ross AJ, Ansley SJ, Hoskins BE, Kirsten B, Mein CA, Froguel P, Scambler PJ, Lewis RA, Lupski JR, Katsanis N. Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome. Am J Hum Genet. 2003 May;72(5):1187-99.
Badano JL, Kim JC, Hoskins BE, Lewis RA, Ansley SJ, Cutler DJ, Castellan C, Beales PL, Leroux MR, Katsanis N. Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus. Hum Mol Genet. 2003 Jul 15;12(14):1651-9.
Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, Kim JC, Ross AJ, Eichers ER, Teslovich TM, Mah AK, Johnsen RC, Cavender JC, Lewis RA, Leroux MR, Beales PL, Katsanis N. Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature. 2003 Oct 9;425(6958):628-33.
Kim J-C, Badano JL, Sibold S, Esmail MA, Hill J, Hoskins BE, Leitch CC, Venner K, Ansley SJ, Ross AJ, Leroux MR, Katsanis N, Beales PL. The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nat Genet. 2004 May;36(5):462-70.
Li JB, Gerdes JM, Haycraft CJ, Fan Y, Teslovich TM, May-Simera H, Li H, Blacque OE, Li L, Leitch CC, Lewis RA, Green JS, Parfrey PS, Leroux MR, Davidson WS, Beales PL, Guay-Woodford LM, Yoder BK, Stormo GD, Katsanis N, Dutcher SK. Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell. 2004 May 14;117(4):541-42.
Blacque OE, Reardon MJ, McCarthy J, Li C, Mahjoub MR, Ansley SL, Badano JL, Mah AK, Beales PL, Davidson WS, Johnsen RC, Audeh M, Plasterk RHA, Baille DL, Katsanis N, Quarmby LM, Wicks SR, Leroux MR. Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport. Genes Dev. 2004 Jul 1;18(13):1630-42.
Fan Y, Esmail MA, Ansley SJ, Blacque OE, Boroevich K, Ross AJ, Moore SJ, Badano JL, May-Simera H, Compton DS, Green JS, Lewis RA, van Haelst MM, Parfrey PS, Baillie DL, Beales PL, Katsanis N, Davidson WS, Leroux MR. Mutations in a member of the Ras superfamily of small GTP-binding proteins
causes Bardet-Biedl syndrome. Nat Genet. 2004 Sep;36(9):989-93.
Kulaga HM, Leitch CC, Eichers ER, Badano JL, Lesemann A, Hoskins BE, Lupski JR, Beales PL, Reed RR, Katsanis N. Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse. Nat Genet. 2004 Sep;36(9):994-8.
Badano JL, Teslovich TM, Katsanis N. The centrosome in human genetic disease. Nat Rev Genet. 2005 Mar;6(3):194-205.
Contact Information:
Nicholas Katsanis, Ph.D.
Johns Hopkins University School of Medicine
Institute of Genetic Medicine
733 N Broadway
Broadway Research Building,Room 533
Baltimore, MD 21287
Phone: (410) 502-6660
Fax: (410) 502-7543
E-Mail: katsanis@jhmi.edu
