title: A novel mutation disrupting the cytoplasmic domain of CRB1 in a large consanguineous family of Palestinian origin affected with Leber congenital amaurosis.
abstract: Leber congenital amaurosis (LCA) is a genetically heterogeneous autosomal recessive condition responsible for congenital blindness or greatly impaired vision since birth. Eight LCA loci have been mapped, but only six out of eight genes have been hitherto identified. A genome-wide screen for homozygosity was conducted in a large consanguineous family originating from Palestine, for which no mutation was found in any of the six known LCA genes and that excluded the LCA3 and LCA5 loci. Evidence for homozygosity, however, was found in all affected patients of the family on chromosome 1q31, a region in which the human homologue of the Drosophila melanogaster crumbs gene (CRB1) has been mapped. Consequently, we proposed a hypothesis that the disease-causing mutation in this family might lie in an unexplored region of this LCA gene. As a matter of fact, while no mutation was found in any of the 11 CRB1 exons originally reported, we identified a 10-bp (del 4121-4130) deletion segregating with the disease in a later reported 12th exon lying in the 3' end of the gene. Interestingly, this deletion disrupts an amino acid sequence that was shown to be crucial for the function of the protein in the Drosophila counterpart (CRB).
authors.affiliation: Unité de Recherches sur les Handicaps Génétiques de l'Enfant, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Gerber
authors.forename: Isabelle
authors.initials: I
authors.lastname: Perrault
authors.forename: Sylvain
authors.initials: S
authors.lastname: Hanein
authors.forename: Stavit
authors.initials: S
authors.lastname: Shalev
authors.forename: Joel
authors.initials: J
authors.lastname: Zlotogora
authors.forename: Fabienne
authors.initials: F
authors.lastname: Barbet
authors.forename: Dominique
authors.initials: D
authors.lastname: Ducroq
authors.forename: Jean
authors.initials: J
authors.lastname: Dufier
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Jean
authors.initials: J
authors.lastname: Rozet
authors.forename: Josseline
authors.initials: J
authors.lastname: Kaplan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018912:Arabs / Q000235:genetics*; D001483:Base Sequence; D001766:Blindness / Q000151:congenital*; D020090:Chromosome Segregation; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005136:Eye Proteins; D005260:Female; D006801:Humans; D007557:Israel / Q000453:epidemiology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins; D029242:Optic Atrophy, Hereditary, Leber / Q000208:ethnology / Q000235:genetics*; D010375:Pedigree; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
chemical_list: C448939:CRB1 protein, human; D005136:Eye Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger