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 function1,2,3,4,5. 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.
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Change history
26 June 2008
In the version of this article initially published, the name of the seventh author was misspelled. The correct author name is Majid Alfadhel. The error has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
We thank the individuals with BBS and their families for their continued support and encouragement. We also thank J. Gerdes for her thoughtful comments on the manuscript. This work was supported by grant R01HD04260 from the US National Institute of Child Health and Development (N.K.); by R01DK072301 and R01DK075972 (N.K.) and National Research Service Award fellowship F32 DK079541-01 (E.E.D.) from the National Institute of Diabetes and Digestive and Kidney Diseases by a grant from the Polycystic Kidney Disease Foundation (J.L.B. and N.K.); by the Programme ANR maladies rares (H.D.) of the French Agence Nationale pour la Recherche; and by Newlife and the Medical Research Council UK (P.L.B.). R.A.L. is a Senior Scientific Investigator of Research to Prevent Blindness, New York. P.L.B. is a Senior Wellcome Trust Fellow.
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Leitch, C., Zaghloul, N., Davis, E. et al. Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat Genet 40, 443–448 (2008). https://doi.org/10.1038/ng.97
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DOI: https://doi.org/10.1038/ng.97
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