title: Mutations of the CEP290 gene encoding a centrosomal protein cause Meckel-Gruber syndrome.
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.
authors: Department of Human Genetics, RWTH Aachen University, Aachen, Germany.
authors: Valeska
authors: V
authors: Frank
authors: Anneke I
authors: AI
authors: den Hollander
authors: Nadina Ortiz
authors: NO
authors: Brüchle
authors: Marijke N
authors: MN
authors: Zonneveld
authors: Gudrun
authors: G
authors: Nürnberg
authors: Christian
authors: C
authors: Becker
authors: Gabriele
authors: G
authors: Du Bois
authors: Heide
authors: H
authors: Kendziorra
authors: Susanne
authors: S
authors: Roosing
authors: Jan
authors: J
authors: Senderek
authors: Peter
authors: P
authors: Nürnberg
authors: Frans P M
authors: FP
authors: Cremers
authors: Klaus
authors: K
authors: Zerres
authors: Carsten
authors: C
authors: Bergmann
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000235:genetics*; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002490:Central Nervous System / Q000002:abnormalities; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D006239:Haplotypes; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics; D008099:Liver / Q000002:abnormalities; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D013577:Syndrome
chemical_list: D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins