Rando L. Allikmets, PhD

  • William and Donna Acquavella Professor of Ophthalmic Sciences (in Ophthalmology and Pathology and Cell Biology)
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Overview

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.

Email: rla22@cumc.columbia.edu

Academic Appointments

  • William and Donna Acquavella Professor of Ophthalmic Sciences (in Ophthalmology and Pathology and Cell Biology)

Administrative Titles

  • Research Director, Edward S. Harkness Eye Institute

Credentials & Experience

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

Research

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.

Staff

Assistant Professor:

Takayuki Nagasaki, Ph.D.

Associate Research Scientist:

Jian Kong, M.D.

Jana Zernant, Ph.D.

Staff Associate:

Pei-Yin Su, M.S.

Postdoctoral Research Scientist:

Winston Lee, Ph.D.

Technician:

Yan Li, B.A.

 

 

Research Interests

  • Gene- and small molecule therapy for retinal disorders.
  • Genetic studies of Mendelian and complex eye diseases (Stargardt macular dystrophy and more)
  • Microarray-based, next generation sequencing-based diagnostic applications for eye diseases

Selected Publications

  • 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.