Pleiotropic Effects of CEP290 ( NPHP6) Mutations Extend to Meckel Syndrome

• Published in: American journal of human genetics Vol. 81; no. 1; pp. 170 - 179
• Main Authors: Baala, Lekbir, Audollent, Sophie, Martinovic, Jéléna, Ozilou, Catherine, Babron, Marie-Claude, Sivanandamoorthy, Sivanthiny, Saunier, Sophie, Salomon, Rémi, Gonzales, Marie, Rattenberry, Eleanor, Esculpavit, Chantal, Toutain, Annick, Moraine, Claude, Parent, Philippe, Marcorelles, Pascale, Dauge, Marie-Christine, Roume, Joëlle, Merrer, Martine Le, Meiner, Vardiella, Meir, Karen, Menez, Françoise, Beaufrère, Anne-Marie, Francannet, Christine, Tantau, Julia, Sinico, Martine, Dumez, Yves, MacDonald, Fiona, Munnich, Arnold, Lyonnet, Stanislas, Gubler, Marie-Claire, Génin, Emmanuelle, Johnson, Colin A., Vekemans, Michel, Encha-Razavi, Férechté, Attié-Bitach, Tania
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.07.2007; University of Chicago Press; Cell Press; American Society of Human Genetics
• Subjects: Abnormalities, Multiple - genetics; Abnormalities, Multiple - pathology; Antigens, Neoplasm - genetics; Biological and medical sciences; Brain - abnormalities; Chromosomes; DNA Mutational Analysis; Female; Fundamental and applied biological sciences. Psychology; Gene expression; Gene loci; General aspects. Genetic counseling; Genetics of eukaryotes. Biological and molecular evolution; Haplotypes; Humans; Liver - abnormalities; Liver - pathology; Lod Score; Male; Malformations of the nervous system; Medical genetics; Medical sciences; Molecular and cellular biology; Multicystic Dysplastic Kidney - genetics; Multicystic Dysplastic Kidney - pathology; Mutation; Neoplasm Proteins - genetics; Neurological disorders; Neurology; Pedigree; Polydactyly - genetics; Portal System - abnormalities; Syndrome; Human; Nervous system diseases; Urinary system disease; Malformation; Diseases of the osteoarticular system; Digestive diseases; Genetics; Mutation; Meckel syndrome; Genetic disease
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/519494

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.