Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

A Corrigendum to this article was published on 01 July 2008

This article has been updated

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Developmental defects in mks1 morphant embryos.
Figure 2: Defective gastrulation movements in zebrafish mks1 morphants.
Figure 3: Developmental defects in mks3 morphant embryos.
Figure 4: Genetic interaction of mks3 and cep290.

Accession codes

Accessions

GenBank/EMBL/DDBJ

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.

References

  1. Baala, L. et al. Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome. Am. J. Hum. Genet. 81, 170–179 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Dawe, H.R. et al. The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. Hum. Mol. Genet. 16, 173–186 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Delous, M. et al. The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome. Nat. Genet. 39, 875–881 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Kyttala, M. et al. MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome. Nat. Genet. 38, 155–157 (2006).

    Article  PubMed  Google Scholar 

  5. Smith, U.M. et al. The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat. Genet. 38, 191–196 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Badano, J.L., Mitsuma, N., Beales, P.L. & Katsanis, N. The ciliopathies: an emerging class of human genetic disorders. Annu. Rev. Genomics Hum. Genet. 7, 125–148 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Stoetzel, C. et al. Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome. Am. J. Hum. Genet. 80, 1–11 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Badano, J.L. et al. Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus. Hum. Mol. Genet. 12, 1651–1659 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Beales, P.L. et al. Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome. Am. J. Hum. Genet. 72, 1187–1199 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Katsanis, N. et al. Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder. Science 293, 2256–2259 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Stoetzel, C. et al. BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus. Nat. Genet. 38, 521–524 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Badano, J.L. et al. Dissection of epistasis in oligogenic Bardet-Biedl syndrome. Nature 439, 326–330 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Davis, E.E., Brueckner, M. & Katsanis, N. The emerging complexity of the vertebrate cilium: new functional roles for an ancient organelle. Dev. Cell 11, 9–19 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Ross, A.J. et al. Disruption of Bardet-Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebrates. Nat. Genet. 37, 1135–1140 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Gerdes, J.M. et al. Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt response. Nat. Genet. 39, 1350–1360 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Khaddour, R. et al. Spectrum of MKS1 and MKS3 mutations in Meckel syndrome: a genotype-phenotype correlation. [Online]. Hum. Mutat. 28, 523–524 (2007).

    Article  PubMed  Google Scholar 

  17. Gherman, A., Davis, E.E. & Katsanis, N. The ciliary proteome database: an integrated community resource for the genetic and functional dissection of cilia. Nat. Genet. 38, 961–962 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Arts, H.H. et al. Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome. Nat. Genet. 39, 882–888 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Sayer, J.A. et al. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat. Genet. 38, 674–681 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Vierkotten, J., Dildrop, R., Peters, T., Wang, B. & Ruther, U. Ftm is a novel basal body protein of cilia involved in Shh signalling. Development 134, 2569–2577 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Karmous-Benailly, H. et al. Antenatal presentation of Bardet-Biedl syndrome may mimic Meckel syndrome. Am. J. Hum. Genet. 76, 493–504 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ramensky, V., Bork, P. & Sunyaev, S. Human non-synonymous SNPs: server and survey. Nucleic Acids Res. 30, 3894–3900 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Beales, P.L., Elcioglu, N., Woolf, A.S., Parker, D. & Flinter, F.A. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J. Med. Genet. 36, 437–446 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Baala, L. et al. The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome. Am. J. Hum. Genet. 80, 186–194 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. den Hollander, A.I. et al. Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am. J. Hum. Genet. 79, 556–561 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Helou, J. et al. Mutation analysis of NPHP6/CEP290 in patients with Joubert syndrome and Senior-Loken syndrome. J. Med. Genet. 44, 657–663 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Katsanis, N. et al. Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet-Biedl syndrome. Nat. Genet. 26, 67–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Stone, D.L. et al. Mutation of a gene encoding a putative chaperonin causes McKusick-Kaufman syndrome. Nat. Genet. 25, 79–82 (2000).

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nicholas Katsanis.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9 and Supplementary Table 1 (PDF 42439 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.97

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing