- William and Donna Acquavella Professor of Ophthalmic Sciences (in Ophthalmology and Pathology and Cell Biology)
- Research Director, Edward S. Harkness Eye Institute
Since the entire sequence of the human genome has become available, our goal is to use this information to assess the whole range of genetic variation in the human population. This will allow us to answer a myriad of questions, including the most immediate: Which genetic variants (or their combinations) predispose humans to different inherited disorders? Our laboratory focuses on discovering genetic defects underlying Mendelian and complex disorders with special emphasis on eye diseases.
The first step in discovering the underlying mechanisms of a disorder is the cloning and characterization of the relevant gene(s) and determining the mutation spectrum, causative for each individual phenotype. This goal is achieved in our lab by systematic screening of candidate genes on large collections of patient DNA with semi-automated, high-throughput mutation detection and genotyping technologies. Among candidate genes under analysis, we are specifically interested in those that belong to the ATP-binding cassette (ABC) transporter superfamily. Members of this family are ubiquitous membrane proteins that carry out vital transport functions in all cells and cellular organelles. We have succeeded in defining several ABC genes as involved in various human inherited diseases (ABCR, ABC7) and in important cellular functions such as multi-drug resistance during cancer chemotherapy (ABCP). The discovery of ABCR, a rod photoreceptor-specific transporter of retinoids, has significantly advanced our knowledge of molecular genetic basis of several retinal diseases including Stargardt macular dystrophy (STGD), cone-rod dystrophy (CRD), retinitis pigmentosa (RP19), and age-related macular degeneration (AMD).
Major research objectives of the laboratory are: (1) cloning and mutational analysis of genes involved in eye disorders of Mendelian inheritance; (2) association analysis of genetic variation in candidate genes for complex disorders, such as age-related macular degeneration (AMD); (3) development of microarray-based screening technologies and new approaches for ABC gene therapy.
The Laboratory of Molecular Genetics implements a three-step translational, "from bench to bedside", program consisting of discovering the genetic cause of retinal disease, developing advanced methods for molecular diagnostics and, finding efficient treatment options for precisely diagnosed patients.
The first step in discovering the underlying mechanisms of any disorder is the cloning and characterization of the relevant gene(s) and determining the mutation spectrum causative for each individual phenotype. This goal is achieved by a combination of classical genetic methods from linkage analysis to association studies of candidate genes on large collections of patient DNA with semi-automated, high-throughput mutation detection and genotyping technologies. Some genes/loci discovered in the laboratory include the gene responsible for Stargardt disease and cone-rod dystrophy, ABCA4 (ABCR), and susceptibility loci for age-related macular degeneration containing genes involved in complement response, factor H (CFH), factor B (CFB), and complement component 2 (C2).
Diagnostic screening technologies developed in the laboratory include microarray-based "gene chips" and "disease chips", and next-generation sequencing based gene and disease panels, where all variants from all genes responsible for all known retinal diseases are screened in one step.
Therapeutic approaches include lentiviral gene therapy for Stargardt macular dystrophy and other retinal diseases and modulating the visual cycle by small molecule compounds. In summary, the laboratory provides comprehensive gene discovery, diagnostic and treatment programs for many eye diseases.
Associate Research Scientist:
Mihai Busuioc, M.A., O.D., M.D.
Jian Kong, M.D.
Jana Zernant, M.S.
Angela Xie, M.S.
Carolyn Cai, B.A.
Clinical Research Coordinator:
Winston Lee, M.A.
Lisa Rehm, MPA
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Edward S. Harkness Eye Institute Research Annex160 Fort Washington Avenue
2nd Floor, Room 202
New York, NY 10032
- (212) 305-8989
- (212) 305-7014
Honors & Awards
- 2012 Dario Lorenzetti Lecture, McGill University, Montreal, Canada
- 2010 Foundation Fighting Blindness Visionary Award
- 2008 Mette Warburg Lecture, the Kennedy Center, University of Copenhagen, Denmark
- 2007 Alcon Research Institute Award
- 2006 Awarded the title of “Godfather”, Association DMLA (AMD), Paris, France
- 2005 Foundation Fighting Blindness Annual Trustees Award
- 1998 SAIC 1997 Publication Prize for Biochemistry and Molecular Biology
- 1997 SAIC Science Achievement Award
- Genetic studies of Mendelian and complex eye diseases (Stargardt macular dystrophy, Macular Telangiectasia, age-related macular degeneration, etc.)
- Development of microarray-based and next generation sequencing-based diagnostic applications for eye diseases.
- Gene- and small molecule therapy for retinal disorders.
INTEGRATED CLINICAL, GENETIC AND FUNCTIONAL ANALYSIS OF THE ABCA4 LOCUS (Federal Gov)
Jun 1 2019 - Mar 31 2024
INTEGRATED ANALYSIS OF GENETIC AND CLINICAL DATA FOR RATIONAL CLINICAL TRIALS OF STARGARDT DISEASE (Private)
Dec 1 2018 - Nov 30 2023
STARGARDT DISEASE WITH LOW LIPOFUSCIN (Federal Gov)
Mar 1 2019 - Dec 31 2022
QUANTITATIVE FUNDUS AUTOFLUORESCENCE IN RETINAL DISORDERS (Federal Gov)
Mar 1 2019 - Dec 31 2022
PRECISION MEDICINE FOR ABCA4 DISEASE: MODIFIER ALLELES (Federal Gov)
Jul 1 2018 - May 31 2022
THERAPEUTIC APPROACHES FOR ABCA4-ASSOCIATED DISORDERS (Federal Gov)
Aug 1 2011 - Jul 31 2017
GENETIC SUSCEPTIBILITY TO AGE-RELATED MACULAR DEGENERATION (Federal Gov)
May 1 2001 - Aug 31 2016
COMPLETING GENETIC ANALYSIS OF THE ABCA4 LOCUS (Federal Gov)
Apr 1 2011 - Mar 31 2016
GREATER NEW YORK REGINAL RESEARCH CENTER FOR THE STUDY OF RETINAL DEGENERATIVE (Private)
Jul 1 2010 - Jun 30 2015
DETERMINING THE GENETIC CAUSE OF CENTRAL SEROUS CHORIORETINOPATHY (Private)
Jan 1 2009 - Dec 31 2013
EYEGENE STUDY (Federal Gov)
Oct 1 2007 - Oct 31 2013
GENETICS STUDY PROTOCOL OF MACULAR TELANGECTASIA (Private)
Oct 1 2007 - Oct 1 2013
DEVELOPMENT OF COMPLEMENT MODULATING THERAPEUTIC FOR AMD (Federal Gov)
Aug 1 2009 - Jul 31 2012
GENETICS DIAGNOSTICS CENTER FOR EYE DISEASES (Private)
Sep 1 2009 - May 31 2011
- The AMD Gene Consortium, including Allikmets, R., Seven new loci associated with age-related macular degeneration. Nature Genetics 45:433-439, 2013.
- Dobri, N., Qin, Q., Kong, J., Yamamoto, K., Liu, Z., Moiseyev, G., Ma, J.X., Allikmets, R., Sparrow, J.R., and Petrukhin, K. A1120, a nonretinoid RBP4 antagonist, inhibits formation of cytotoxic bisretinoids in the animal model of enhanced retinal lipofuscinogenesis. Invest. Ophthalmol. Vis. Sci. 54:85-95, 2013.
- Burke, T.R. and Allikmets, R. Author response: Retinal phenotypes in patients homozygous for the G1961E mutation in the ABCA4 gene. Invest. Ophthalmol. Vis. Sci. 54:521, 2013.
- Parmalee, N.L., Schubert, C., Figueroa, M., Bird, A.C., Peto, T., Gillies, M.C. Bernstein, P.S., Kiryluk, K., Terwilliger, J.D., and Allikmets, R. Identification of a potential susceptibility locus for Macular Telangiectasia type 2. PLoS ONE, 7(8):e24268. Epub 2012 Aug 31, 2012.
- Smith, R.T., Merriam, J.E., Sohrab, M.A., Barile, G.R., Blonska, A.M., Haans, R., Pumariega, N.M., Madigan, D., and Allikmets, R. Complement factor H 402H variant and reticular macular disease. Arch. Ophthalmol. 129:1061-1066, 2011.
- Neale, B.M., Fagerness, J., Reynolds, R., Sobrin, L., Parker, M., Raychaudhuri, S., Tan, P.L., Oh, E.C., Merriam, J.E., Souied, E., Bernstein, P.S., Li, B., Frederick, J.M., Zhang, K., Brantley, M.A. Jr, Lee, A.Y., Zack, D.J., Campochiaro, B., Campochiaro, P., Ripke, S., Smith, R.T., Barile, G.R., Katsanis, N., Allikmets, R., Daly. M.J. and Seddon, J.M. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc. Natl. Acad. Sci. USA 107:7395-400, 2010.
- Allikmets, R., Dean, M., Hageman, G.S., Baird, P.N., Klaver, C.C., Bergen, A.A., Weber, B.H. and the International AMD Genetics Consortium. The SERPING1 gene and age-related macular degeneration. Lancet 374:875-876, 2009.
- Allikmets, R., Bergen, A.A., Dean, M., Guymer, R.H., Hageman, G.S., Klaver, C.C., Stefansson, K., Weber, B.H., and International Age-related Macular Degeneration Genetics Consortium. Geographic atrophy in age-related macular degeneration and TLR3. N. Engl. J. Med. 360:2252-4, 2009.
- Allikmets, R. and Dean, M. Bringing age-related macular degeneration into focus. Nature Genetics 40: 820-821, 2008.
- Kong, J., Kim, S.-R., Binley, K., Pata, I., Doi, K., Mannik, J., Zernant-Rajang, J., Kan, O., Iqball, S., Naylor, S., Sparrow, J.R., Gouras, P., and Allikmets R. Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy. Gene Therapy 15:1311-20, 2008.
- Gold, B., Merriam, J.E., Zernant, J., Hancox, L.S., Taiber, A.J., Gehrs, K.M., Cramer, K., Neel, J., Bergeron, J., Barile, G.R., Smith, R.T., the AMD Genetics Clinical Study Group, Hageman, G.S., Dean, M. and Allikmets R. Variation in the Factor B (BF) and Complement Component 2 (C2) Genes in the MHC Class III Locus is Associated with Age-related Macular Degeneration. Nature Genetics 38:458-642, 2006.
- Maiti, P., Kong, J., Kim, S.R., Sparrow, J.R., Allikmets, R., and Rando, R.R. Small Molecule RPE65 Antagonists Limit the Visual Cycle and Prevent Lipofuscin Formation. Biochemistry 45:852-860, 2006.
- Zernant, J., Külm, M., Dharmaraj, S., den Hollander, A.I., Perrault, I., Preising, M.N., Lorenz, B., Kaplan, J., Cremers, F.P.M., Maumenee, I., Koenekoop, R.K., and Allikmets, R. Genotyping microarray (disease chip) for Leber congenital amaurosis: detection of modifier alleles. Invest. Ophthalmol. Vis. Sci. 46:3052-3059, 2005.
- Hageman, G.S., Anderson, D.H., Johnson, L.V., Hancox, L.S., Taiber, A.J., Hardisty, L.I., Hageman, J.L., Stockman, H.A., Borchardt, J.D., Gehrs, K.M., Smith, R.J., Silvestri, G., Russell, S.R., Klaver, C.C.W., Barbazetto, I., Chang, S., Yannuzzi, L.A., Barile, G.R., Merriam, J.C., Smith, R.T., Olsh, A.K., Bergeron, J., Zernant, J., Merriam, J.E., Gold, B., Dean, M. and Allikmets R. A common haplotype in the complement regulatory gene, factor H (HF1/CFH), predisposes individuals to age-related macular degeneration. Proc. Natl. Acad. Sci. USA 102:7227-7232, 2005.
- Jaakson, K., Zernant, J., Külm, M., Hutchinson, A., Tonisson, N, Hawlina, M., Ravnic-Glavac, M., Glavac, D., Meltzer, M., Caruso, R., Testa, F., Maugeri, A., Hoyng, C.B., Gouras, P., Simonelli, F., Lewis, R.A. Lupski, J.R., Cremers, F.P.M., and Allikmets, R. Genotyping microarray (gene chip) for the ABCR (ABCA4) gene. Human Mutation 22:395-403, 2003.
- Zhang, K., Kniazeva, M., Han, M., Li, W., Yu, Z., Yang, Z., Li, Y., Metzker, M.L., Allikmets, R., Zack, D.J., Kakuk, L.E., Lagali, P.S., Wong, P.S., MacDonald, I.M., Sieving, P.A., Figueroa, D., Austin, C.P., Gould, R.J., Ayyagari, R., and Petrukhin, K. A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nature Genetics 27:89-93, 2001.
- Allikmets, R. and the International ABCR Screening Consortium: Further evidence of an association of ABCR alleles with age-related macular degeneration. Am. J. Hum. Genet. 67:487-491, 2000.
- Allikmets, R., Shroyer, N.F., Singh, N., Seddon, J.M., Lewis, R.A., Bernstein, P., Peiffer A., Zabriskie, N., Li, Y., Hutchinson, A., Dean, M., Lupski, J.R., and Leppert, M.: Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science 277:1805-1807, 1997.
- Allikmets, R., Singh, N., Sun, H., Shroyer, N.F., Hutchinson, A., Chidambaram, A., Gerrard, B., Baird, L., Stauffer, D., Peiffer, A., Rattner, A., Smallwood, P., Li, Y., Anderson, K.L., Lewis, R.A., Nathans, J., Leppert, M., Dean, M., and Lupski, J.R.: A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nature Genetics 15:236-246, 1997.