Nature Genetics
23, 217 - 221 (1999)
doi:10.1038/13848
Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12)Anneke I. den Hollander1, Jacoline B. ten Brink2, Yvette J.M. de Kok1, Simone van Soest2, L. Ingeborgh van den Born2, 3, Marc A. van Driel1, Dorien J.R. van de Pol1, Annette M. Payne4, Shomi S. Bhattacharya4, Ulrich Kellner5, Carel B. Hoyng6, Andries Westerveld7, Han G. Brunner1, Elisabeth M. Bleeker-Wagemakers2, August F. Deutman6, John R. Heckenlively8, Frans P.M. Cremers1
& Arthur A.B. Bergen21
Department of Human Genetics, University Hospital Nijmegen, Geert Grooteplein 10, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. 2
The Netherlands Ophthalmic Research Institute, Amsterdam, The Netherlands. 3
The Rotterdam Eye Hospital, Rotterdam, The Netherlands. 4
Institute of Ophthalmology, University College London, London, UK. 5
Department of Ophthalmology, University Clinic Benjamin Franklin, Free University Berlin, Berlin, Germany. 6
Department of Ophthalmology, University Hospital Nijmegen, Nijmegen, the Netherlands. 7
Institute of Human Genetics, University of Amsterdam, Amsterdam, the Netherlands. 8
Department of Ophthalmology, University of California, Los Angeles, California, USA.
Correspondence should be addressed to Frans P.M. Cremers F.Cremers@antrg.azn.nlRetinitis pigmentosa (RP) comprises a clinically and genetically heterogeneous group of diseases that afflicts approximately 1.5 million people worldwide. Affected individuals suffer from a progressive degeneration of the photoreceptors, eventually resulting in severe visual impairment. To isolate candidate genes for chorioretinal diseases, we cloned cDNAs specifically or preferentially expressed in the human retina and the retinal pigment epithelium (RPE) through a novel suppression subtractive hybridization (SSH) method1,
2. One of these cDNAs (RET3C11) mapped to chromosome 1q31−q32.1, a region harbouring a gene involved in a severe form of autosomal recessive RP characterized by a typical preservation of the para-arteriolar RPE (RP12; ref. 3). The full-length cDNA encodes an extracellular protein with 19 EGF-like domains, 3 laminin A G-like domains and a C-type lectin domain. This protein is homologous to the Drosophila melanogaster protein crumbs (CRB), and denoted CRB1 (crumbs homologue 1). In ten unrelated RP patients with preserved para-arteriolar RPE, we identified a homozygous AluY insertion disrupting the ORF, five homozygous missense mutations and four compound heterozygous mutations in CRB1. The similarity to CRB suggests a role for CRB1 in cell-cell interaction and possibly in the maintenance of cell polarity in the retina. The distinct RPE abnormalities observed in RP12 patients suggest that CRB1 mutations trigger a novel mechanism of photoreceptor degeneration.
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