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Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel‐Gruber syndrome
Author(s) -
Frank Valeska,
den Hollander Anneke I.,
Brüchle Nadina Ortiz,
Zonneveld Marijke N.,
Nürnberg Gudrun,
Becker Christian,
Du Bois Gabriele,
Kendziorra Heide,
Roosing Susanne,
Senderek Jan,
Nürnberg Peter,
Cremers Frans P.M.,
Zerres Klaus,
Bergmann Carsten
Publication year - 2008
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20614
Subject(s) - ciliopathies , joubert syndrome , biology , genetics , frameshift mutation , ciliopathy , disease gene identification , nephronophthisis , cilium , polydactyly , nonsense mutation , phenotype , genetic heterogeneity , positional cloning , bardet–biedl syndrome , gene , missense mutation , exome sequencing
Abstract Meckel‐Gruber syndrome (MKS) is an autosomal recessive, lethal multisystemic disorder characterized by meningooccipital encephalocele, cystic kidney dysplasia, hepatobiliary ductal plate malformation, and postaxial polydactyly. Recently, genes for MKS1 and MKS3 were identified, putting MKS on the list of ciliary disorders (ciliopathies). By positional cloning in a distantly related multiplex family, we mapped a novel locus for MKS to a 3‐Mb interval on 12q21. Sequencing of the CEP290 gene located in the minimal critical region showed a homozygous 1‐bp deletion supposed to lead to loss of function of the encoded centrosomal protein CEP290/nephrocystin‐6. CEP290 is thought to be involved in chromosome segregation and localizes to cilia, centrosomes, and the nucleus. Subsequent analysis of another consanguineous multiplex family revealed homozygous haplotypes and the same frameshift mutation. Our findings add to the increasing body of evidence that ciliopathies can cause a broad spectrum of disease phenotypes, and pleiotropic effects of CEP290 mutations range from single organ involvement with isolated Leber congenital amaurosis to Joubert syndrome and lethal early embryonic multisystemic malformations in Meckel‐Gruber syndrome. We compiled clinical and genetic data of all patients with CEP290 mutations described so far. No clear‐cut genotype–phenotype correlations were apparent as almost all mutations are nonsense, frameshift, or splice‐site changes and scattered throughout the gene irrespective of the patients' phenotypes. Conclusively, other factors than the type and location of CEP290 mutations may underlie phenotypic variability. Hum Mutat 29(1), 45–52, 2008. © 2007 Wiley‐Liss, Inc.