title: Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome.
abstract: 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.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733. N Broadway, Baltimore, Maryland 21205, USA.
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Leitch
authors.forename: Norann A
authors.initials: NA
authors.lastname: Zaghloul
authors.forename: Erica E
authors.initials: EE
authors.lastname: Davis
authors.forename: Corinne
authors.initials: C
authors.lastname: Stoetzel
authors.forename: Anna
authors.initials: A
authors.lastname: Diaz-Font
authors.forename: Suzanne
authors.initials: S
authors.lastname: Rix
authors.forename: Majid
authors.initials: M
authors.lastname: Alfadhel
authors.forename: Majid
authors.initials: M
authors.lastname: Al-Fadhel
authors.forename: Richard Alan
authors.initials: RA
authors.lastname: Lewis
authors.forename: Wafaa
authors.initials: W
authors.lastname: Eyaid
authors.forename: Eyal
authors.initials: E
authors.lastname: Banin
authors.forename: Helene
authors.initials: H
authors.lastname: Dollfus
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
authors.forename: Jose L
authors.initials: JL
authors.lastname: Badano
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics*; D020788:Bardet-Biedl Syndrome / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D004677:Encephalocele / Q000235:genetics*; D005260:Female; D054262:Gastrulation; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D010375:Pedigree; D011247:Pregnancy; D011506:Proteins / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; D003598:Cytoskeletal Proteins; C509165:MKS1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011506:Proteins; C468846:TMEM67 protein, human