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

Carmen C. Leitch, Norann A. Zaghloul, Erica Ellen Davis, Corinne Stoetzel, Anna Diaz-Font, Suzanne Rix, Majid Al-Fadhel, Richard Alan Lewis, Wafaa Eyaid, Eyal Banin, Helene Dollfus, Philip L. Beales, Jose L. Badano, Elias Nicholas Katsanis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

285 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)443-448
Number of pages6
JournalNature Genetics
Volume40
Issue number4
DOIs
StatePublished - Apr 2008

ASJC Scopus subject areas

  • Genetics

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