Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12)

Retinitis pigmentosa (RP) comprises a clinically and genetically heterogene ous group of diseases that afflicts approximately 1.5 million people worldw ide. Affected individuals suffer from a progressive degeneration of the pho toreceptors, eventually resulting in severe visual impairment. To isolate c andidate genes for chorioretinal diseases, we cloned cDNAs specifically or preferentially expressed in the human retina and the retinal pigment epithe lium (RPE) through a novel suppression subtractive hybridization (SSH) meth od(1,2). One of these cDNAs (RET3C11) mapped to chromosome 1q31-q32.1, a re gion harbouring a gene involved in a severe form of autosomal recessive RP characterized by a typical preservation of the para-arteriolar RPE (RP12; r ef. 3). The full-length cDNA encodes an extracellular protein with 19 EGF-l ike domains, 3 laminin A G-like domains and a C-type lectin domain. This pr otein is homologous to the Drosophila melanogaster protein crumbs (CRB), an d denoted CRB1 (crumbs homologue 1). In ten unrelated RP patients with pres erved para-arteriolar RPE, we identified a homozygous AluY insertion disrup ting the ORF, five homozygous missense mutations and four compound heterozy gous mutations in CRB1. The similarity to CRB suggests a role for CRB1 in c ell-cell interaction and possibly in the maintenance of cell polarity in th e retina. The distinct RPE abnormalities observed in RP12 patients suggest that CRB1 mutations trigger a novel mechanism of photoreceptor degeneration .