Our Researchers
Robert Koenekoop, MD, PhD
Medical Genetics and Genomics AxisResearch Focus
Human retinal dystrophies (including Leber congenital amaurosis and retinitis pigmentosa) cause blindness in millions of people by photoreceptor death and are genetically and clinically heterogeneous. Currently, over 50 genes have been identified (which describe approximately 50% of the patients), encoding retinal proteins that participate in a wide variety of crucial retinal functional pathways. At least half of the genes remain to be discovered. One of the known genes, RPE65, was recently replaced by subretinal injection of viral particles in a human clinical trial and shown to rescue both vision and photoreceptor function, giving a major impetus to finding all the retinal dystrophy genes. Our goals are to identify new genes that cause human blindness, using a wide variety of techniques including linkage analysis of large families, whole genome scanning and homozygosity mapping using SNP microarrays in single patients and candidate gene aprroaches. This combined approach has allowed us to discover 5 new genes thusfar, including CEP290, LCA5 and LCA3 for Leber congenital amaurosis and RP25 and TOPORS1 for retinitis pigmentosa. These new genes and their respective proteins have given new insights into both normal retinal functioning and the molecular mechanisms of retinal blindness. At the same time these new genes are candidates for further gene replacement in humans suffering from these devastating diseases.
Keywords
Blindness, hereditary retinal diseases, retinitis pigmentosa, Leber congenital amaurosis, genotype-phenotype correlations, SNP microarrays, homozygosity mapping, linkage analysis
Selected Publications
Identification of novel mutations in patients with Leber congenital amaurosis and juvenile RP by genome-wide homozygosity mapping with SNP microarrays. den Hollander AI, Lopez I, Yzer S, Zonneveld MN, Janssen IM, Strom TM, Hehir-Kwa JY, Veltman JA, Arends ML, Meitinger T, Musarella MA, van den Born LI, Fishman GA, Maumenee IH, Rohrschneider K, Cremers FP, Koenekoop RK. Invest Ophthalmol Vis Sci. 2007;48:5690-5698.
Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis. den Hollander AI, Koenekoop RK, Mohamed MD, Arts HH, Boldt K, Towns KV, Sedmak T, Beer M, Nagel-Wolfrum K, McKibbin M, Dharmaraj S, Lopez I, Ivings L, Williams GA, Springell K, Woods CG, Jafri H, Rashid Y, Strom TM, van der Zwaag B, Gosens I, Kersten FF, van Wijk E, Veltman JA, Zonneveld MN, van Beersum SE, Maumenee IH, Wolfrum U, Cheetham ME, Ueffing M, Cremers FP, Inglehearn CF, Roepman R. Nature Genetics. 2007;39: 889-895. Epub 2007 Jun 3.
Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. den Hollander AI, Koenekoop RK, Yzer S, Lopez I, Arends ML, Voesenek KE, Zonneveld MN, Strom TM, Meitinger T, Brunner HG, Hoyng CB, van den Born LI, Rohrschneider K, Cremers FP. Am J Hum Genet. 2006;79:556-561. Epub 2006 Jul 11.
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