title: Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype.
abstract: Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration responsible for congenital blindness. Hitherto, 13 LCA genes have been mapped, nine of which have been identified. Recently, mutations in the NPHP6/CEP290 gene were shown to account for Joubert and Senior-Loken syndromes and to represent a frequent cause of isolated LCA. All LCA patients shared an intronic mutation resulting in an aberrantly spliced transcript and low levels of wild-type transcript that was believed to explain the absence of cerebellar and renal involvement in these patients. Here, we confirm the high frequency of NPHP6/CEP290 mutations in our series of LCA families hailing worldwide (22%). However, we show that conversely to other LCA genes, NPHP6 is involved in families of European descent only (38/38). A total of 24 different mutations were found, 23 of which are novel (one founder mutation in the North region of France). All mutations but two were either nonsense, frameshift, or splice-site changes. The common NPHP6/CEP290 intronic mutation accounted for 43% (33/76) of all disease alleles. Twelve families did not carry this common intronic mutation. At least 10 out of them harboured two mutations expected to truncate the protein questioning the relevance of the assumption according to which the retinal-restricted phenotype in LCA patient could be due to a residual NPHP6/CEP290 activity. Finally, we show that all patients were affected with the cone-rod subtype of the disease whatever their NPHP6/CEP290 genotype.
authors.affiliation: Unité de Recherches en Génétique et Epigénétique des Maladies Métaboliques, Neurosensorielles et du Développement, INSERM U78, Hôpital des Enfants Malades, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Perrault
authors.forename: Nathalie
authors.initials: N
authors.lastname: Delphin
authors.forename: Sylvain
authors.initials: S
authors.lastname: Hanein
authors.forename: Sylvie
authors.initials: S
authors.lastname: Gerber
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Dufier
authors.forename: Olivier
authors.initials: O
authors.lastname: Roche
authors.forename: Sabine
authors.initials: S
authors.lastname: Defoort-Dhellemmes
authors.forename: Hélène
authors.initials: H
authors.lastname: Dollfus
authors.forename: Elisa
authors.initials: E
authors.lastname: Fazzi
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Josseline
authors.initials: J
authors.lastname: Kaplan
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Rozet
mesh_terms: D000328:Adult; D000483:Alleles; D000951:Antigens, Neoplasm / Q000235:genetics*; D018797:Cell Cycle Proteins; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins; D005091:Exons; D016368:Frameshift Mutation; D006801:Humans; D007223:Infant; D007438:Introns; D015810:Linkage Disequilibrium; D009363:Neoplasm Proteins / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins