title: Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome.
abstract: Meckel syndrome (MKS) is a rare autosomal recessive lethal condition characterized by central nervous system malformations, polydactyly, multicystic kidney dysplasia, and ductal changes of the liver. Three loci have been mapped (MKS1-MKS3), and two genes have been identified (MKS1/FLJ20345 and MKS3/TMEM67), whereas the gene at the MKS2 locus remains unknown. To identify new MKS loci, a genomewide linkage scan was performed using 10-cM-resolution microsatellite markers in eight families. The highest heterogeneity LOD score was obtained for chromosome 12, in an interval containing CEP290, a gene recently identified as causative of Joubert syndrome (JS) and isolated Leber congenital amaurosis. In view of our recent findings of allelism, at the MKS3 locus, between these two disorders, CEP290 was considered a candidate, and homozygous or compound heterozygous truncating mutations were identified in four families. Sequencing of additional cases identified CEP290 mutations in two fetuses with MKS and in four families presenting a cerebro-reno-digital syndrome, with a phenotype overlapping MKS and JS, further demonstrating that MKS and JS can be variable expressions of the same ciliopathy. These data identify a fourth locus for MKS (MKS4) and the CEP290 gene as responsible for MKS.
authors.affiliation: Université René Descartes et INSERM U-781, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France.
authors.forename: Lekbir
authors.initials: L
authors.lastname: Baala
authors.forename: Sophie
authors.initials: S
authors.lastname: Audollent
authors.forename: Jéléna
authors.initials: J
authors.lastname: Martinovic
authors.forename: Catherine
authors.initials: C
authors.lastname: Ozilou
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Babron
authors.forename: Sivanthiny
authors.initials: S
authors.lastname: Sivanandamoorthy
authors.forename: Sophie
authors.initials: S
authors.lastname: Saunier
authors.forename: Rémi
authors.initials: R
authors.lastname: Salomon
authors.forename: Marie
authors.initials: M
authors.lastname: Gonzales
authors.forename: Eleanor
authors.initials: E
authors.lastname: Rattenberry
authors.forename: Chantal
authors.initials: C
authors.lastname: Esculpavit
authors.forename: Annick
authors.initials: A
authors.lastname: Toutain
authors.forename: Claude
authors.initials: C
authors.lastname: Moraine
authors.forename: Philippe
authors.initials: P
authors.lastname: Parent
authors.forename: Pascale
authors.initials: P
authors.lastname: Marcorelles
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Dauge
authors.forename: Joëlle
authors.initials: J
authors.lastname: Roume
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.forename: Vardiella
authors.initials: V
authors.lastname: Meiner
authors.forename: Karen
authors.initials: K
authors.lastname: Meir
authors.forename: Françoise
authors.initials: F
authors.lastname: Menez
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Beaufrère
authors.forename: Christine
authors.initials: C
authors.lastname: Francannet
authors.forename: Julia
authors.initials: J
authors.lastname: Tantau
authors.forename: Martine
authors.initials: M
authors.lastname: Sinico
authors.forename: Yves
authors.initials: Y
authors.lastname: Dumez
authors.forename: Fiona
authors.initials: F
authors.lastname: MacDonald
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Gubler
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Génin
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.forename: Michel
authors.initials: M
authors.lastname: Vekemans
authors.forename: Férechté
authors.initials: F
authors.lastname: Encha-Razavi
authors.forename: Tania
authors.initials: T
authors.lastname: Attié-Bitach
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000951:Antigens, Neoplasm / Q000235:genetics*; D001921:Brain / Q000002:abnormalities*; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D005260:Female; D006239:Haplotypes; D006801:Humans; D008099:Liver / Q000002:abnormalities* / Q000473:pathology; D008126:Lod Score; D008297:Male; D021782:Multicystic Dysplastic Kidney / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010375:Pedigree; D017689:Polydactyly / Q000235:genetics*; D011168:Portal System / Q000002:abnormalities*; D013577:Syndrome
chemical_list: D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins