title: Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12).
abstract: Retinitis 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) method. 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.
authors.affiliation: Department of Human Genetics, University Hospital Nijmegen, Geert Grooteplein 10, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: A I
authors.initials: AI
authors.lastname: den Hollander
authors.forename: J B
authors.initials: JB
authors.lastname: ten Brink
authors.forename: Y J
authors.initials: YJ
authors.lastname: de Kok
authors.forename: S
authors.initials: S
authors.lastname: van Soest
authors.forename: L I
authors.initials: LI
authors.lastname: van den Born
authors.forename: M A
authors.initials: MA
authors.lastname: van Driel
authors.forename: D J
authors.initials: DJ
authors.lastname: van de Pol
authors.forename: A M
authors.initials: AM
authors.lastname: Payne
authors.forename: S S
authors.initials: SS
authors.lastname: Bhattacharya
authors.forename: U
authors.initials: U
authors.lastname: Kellner
authors.forename: C B
authors.initials: CB
authors.lastname: Hoyng
authors.forename: A
authors.initials: A
authors.lastname: Westerveld
authors.forename: H G
authors.initials: HG
authors.lastname: Brunner
authors.forename: E M
authors.initials: EM
authors.lastname: Bleeker-Wagemakers
authors.forename: A F
authors.initials: AF
authors.lastname: Deutman
authors.forename: J R
authors.initials: JR
authors.lastname: Heckenlively
authors.forename: F P
authors.initials: FP
authors.lastname: Cremers
authors.forename: A A
authors.initials: AA
authors.lastname: Bergen
mesh_terms: D020087:Alu Elements / Q000235:genetics; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002460:Cell Line; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics*; D005192:Family Health; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009154:Mutation; D010375:Pedigree; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA; D014018:Tissue Distribution
chemical_list: D018076:DNA, Complementary; D029721:Drosophila Proteins; D005136:Eye Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; C064360:crb protein, Drosophila