Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome

• Published in: Nature genetics Vol. 40; no. 4; pp. 443 - 448
• Main Authors: Banin, Eyal, Badano, Jose L, Zaghloul, Norann A, Eyaid, Wafaa, Stoetzel, Corinne, Rix, Suzanne, Diaz-Font, Anna, Beales, Philip L, Katsanis, Nicholas, Alfadhel, Majid, Dollfus, Helene, Leitch, Carmen C, Davis, Erica E, Lewis, Richard Alan
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2008; Nature Publishing Group
• Subjects: Adult; Agriculture; Alternative Splicing; Amino Acid Sequence; Animal Genetics and Genomics; Animals; Antigens, Neoplasm; Antigens, Neoplasm - genetics; Bardet-Biedl Syndrome; Bardet-Biedl Syndrome - genetics; Bardet-Biedl Syndrome - pathology; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Birth defects; Cancer Research; Child; Child, Preschool; Danio rerio; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA Mutational Analysis; Embryo, Nonmammalian; Embryo, Nonmammalian - cytology; Embryo, Nonmammalian - metabolism; Encephalocele; Encephalocele - genetics; Female; Freshwater; Fundamental and applied biological sciences. Psychology; Gastrulation; Gene Function; Gene mutations; Genetic aspects; Genetic disorders; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Health aspects; Homozygote; Human Genetics; Humans; In situ hybridization; letter; Life Sciences; Male; Malformations of the nervous system; Medical sciences; Membrane Proteins; Membrane Proteins - genetics; Molecular biology; Molecular Sequence Data; Mutation; Mutation - genetics; Neoplasm Proteins; Neoplasm Proteins - genetics; Neurology; Pedigree; Pregnancy; Proteins; Proteins - genetics; Risk factors; Sequence Homology, Amino Acid; Syndrome; Zebrafish; Zebrafish - genetics; Zebrafish - growth & development; Zebrafish - metabolism; United States; Endocrinopathy; Obesity; Laurence-Moon-Bardet-Biedl syndrome; Nervous system diseases; Diseases of the osteoarticular system; Nutrition disorder; Congenital disease; Genetic disease; Genital diseases; Cerebral disorder; Encephalocele; Eye disease; Gene; Malformation; Central nervous system disease; Mutation; Complex syndrome; Nutritional status
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.97

Meckel-Gruber syndrome (MKS) is a genetically heterogeneous, neonatally lethal malformation and the most common form of syndromic neural tube defect (NTD). To date, several MKS-associated genes have been identified whose protein products affect ciliary function. Here we show that mutations in MKS1, MKS3 and CEP290 (also known as NPHP6) either can cause Bardet-Biedl syndrome (BBS) or may have a potential epistatic effect on mutations in known BBS-associated loci. Five of six families with both MKS1 and BBS mutations manifested seizures, a feature that is not a typical component of either syndrome. Functional studies in zebrafish showed that mks1 is necessary for gastrulation movements and that it interacts genetically with known bbs genes. Similarly, we found two families with missense or splice mutations in MKS3, in one of which the affected individual also bears a homozygous nonsense mutation in CEP290 that is likely to truncate the C terminus of the protein. These data extend the genetic stratification of ciliopathies and suggest that BBS and MKS, although distinct clinically, are allelic forms of the same molecular spectrum.