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.

  • Letter
  • Published:

Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome

Nature Genetics volume 39, pages 882–888 (2007)Cite this article

Abstract

Protein-protein interaction analyses have uncovered a ciliary and basal body protein network that, when disrupted, can result in nephronophthisis (NPHP), Leber congenital amaurosis, Senior-Løken syndrome (SLSN) or Joubert syndrome (JBTS)1,2,3,4,5,6. However, details of the molecular mechanisms underlying these disorders remain poorly understood. RPGRIP1-like protein (RPGRIP1L) is a homolog of RPGRIP1 (RPGR-interacting protein 1), a ciliary protein defective in Leber congenital amaurosis7,8. We show that RPGRIP1L interacts with nephrocystin-4 and that mutations in the gene encoding nephrocystin-4 (NPHP4) that are known to cause SLSN disrupt this interaction. RPGRIP1L is ubiquitously expressed, and its protein product localizes to basal bodies. Therefore, we analyzed RPGRIP1L as a candidate gene for JBTS and identified loss-of-function mutations in three families with typical JBTS, including the characteristic mid-hindbrain malformation. This work identifies RPGRIP1L as a gene responsible for JBTS and establishes a central role for cilia and basal bodies in the pathophysiology of this disorder.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Structure of RPGRIP1L and RPGRIP1 and their mRNA expression in different tissues.
Figure 2: RPGRIP1L interaction with nephrocystin-4.
Figure 3: Colocalization of RPGRIP1L and nephrocystin-4 in the basal bodies of mammalian cells.
Figure 4: Localization of RPGRIP1L in the retina.
Figure 5: Localization of RPGRIP1L in brain and kidney.
Figure 6: Mapping and sequence analysis of families carrying RPGRIP1L mutations.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Mollet, G. et al. The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin. Nat. Genet. 32, 300–305 (2002).

    Article  CAS  Google Scholar 

  2. Otto, E.A. et al. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat. Genet. 37, 282–288 (2005).

    Article  CAS  Google Scholar 

  3. Roepman, R. et al. Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutations. Proc. Natl. Acad. Sci. USA 102, 18520–18525 (2005).

    Article  CAS  Google Scholar 

  4. 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  Google Scholar 

  5. Parisi, M.A. et al. The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. Am. J. Hum. Genet. 75, 82–91 (2004).

    Article  CAS  Google Scholar 

  6. 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  Google Scholar 

  7. Roepman, R. et al. The retinitis pigmentosa GTPase regulator (RPGR) interacts with novel transport-like proteins in the outer segments of rod photoreceptors. Hum. Mol. Genet. 9, 2095–2105 (2000).

    Article  CAS  Google Scholar 

  8. Dryja, T.P. et al. Null RPGRIP1 alleles in patients with Leber congenital amaurosis. Am. J. Hum. Genet. 68, 1295–1298 (2001).

    Article  CAS  Google Scholar 

  9. Satran, D., Pierpont, M.E. & Dobyns, W.B. Cerebello-oculo-renal syndromes including Arima, Senior-Loken and COACH syndromes: more than just variants of Joubert syndrome. Am. J. Med. Genet. 86, 459–469 (1999).

    Article  CAS  Google Scholar 

  10. Parisi, M.A., Doherty, D., Chance, P.F. & Glass, I.A. Joubert syndrome (and related disorders) (OMIM 213300). Eur. J. Hum. Genet. 15, 511–521 (2007).

    Article  CAS  Google Scholar 

  11. Maria, B.L. et al. Molar tooth sign in Joubert syndrome: clinical, radiologic, and pathologic significance. J. Child Neurol. 14, 368–376 (1999).

    Article  CAS  Google Scholar 

  12. Pellegrino, J.E., Lensch, M.W., Muenke, M. & Chance, P.F. Clinical and molecular analysis in Joubert syndrome. Am. J. Med. Genet. 72, 59–62 (1997).

    Article  CAS  Google Scholar 

  13. Ferland, R.J. et al. Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat. Genet. 36, 1008–1013 (2004).

    Article  CAS  Google Scholar 

  14. 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  Google Scholar 

  15. Fliegauf, M. et al. Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia. J. Am. Soc. Nephrol. 17, 2424–2433 (2006).

    Article  CAS  Google Scholar 

  16. Valente, E.M. et al. Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome. Nat. Genet. 38, 623–625 (2006).

    Article  CAS  Google Scholar 

  17. 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  Google Scholar 

  18. Chang, B. et al. In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouse. Hum. Mol. Genet. 15, 1847–1857 (2006).

    Article  CAS  Google Scholar 

  19. Otto, E. et al. A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution. Am. J. Hum. Genet. 71, 1161–1167 (2002).

    Article  CAS  Google Scholar 

  20. Wolfrum, U. Centrin in the photoreceptor cells of mammalian retinae. Cell Motil. Cytoskeleton 32, 55–64 (1995).

    Article  CAS  Google Scholar 

  21. Rattner, A., Chen, J. & Nathans, J. Proteolytic shedding of the extracellular domain of photoreceptor cadherin. Implications for outer segment assembly. J. Biol. Chem. 279, 42202–42210 (2004).

    Article  CAS  Google Scholar 

  22. Banizs, B. et al. Dysfunctional cilia lead to altered ependyma and choroid plexus function, and result in the formation of hydrocephalus. Development 132, 5329–5339 (2005).

    Article  CAS  Google Scholar 

  23. Doolin, P.F. & Birge, W.J. Ultrastructural organization of cilia and basal bodies of the epithelium of the choroid plexus in the chick embryo. J. Cell Biol. 29, 333–345 (1966).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. Ng, P.C. & Henikoff, S. Predicting deleterious amino acid substitutions. Genome Res. 11, 863–874 (2001).

    Article  CAS  Google Scholar 

  26. Kantardzhieva, A. et al. MPP5 recruits MPP4 to the CRB1 complex in photoreceptors. Invest. Ophthalmol. Vis. Sci. 46, 2192–2201 (2005).

    Article  Google Scholar 

  27. Roepman, R., Schick, D. & Ferreira, P.A. Isolation of retinal proteins that interact with retinitis pigmentosa GTPase regulator by interaction trap screen in yeast. Methods Enzymol. 316, 688–704 (2000).

    Article  CAS  Google Scholar 

  28. van Wijk, E. et al. The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1. Hum. Mol. Genet. 15, 751–765 (2006).

    Article  CAS  Google Scholar 

  29. Brandstatter, J.H., Koulen, P., Kuhn, R., van der, P.H. & Wassle, H. Compartmental localization of a metabotropic glutamate receptor (mGluR7): two different active sites at a retinal synapse. J. Neurosci. 16, 4749–4756 (1996).

    Article  CAS  Google Scholar 

  30. Mogensen, M.M., Malik, A., Piel, M., Bouckson-Castaing, V. & Bornens, M. Microtubule minus-end anchorage at centrosomal and non-centrosomal sites: the role of ninein. J. Cell Sci. 113, 3013–3023 (2000).

    CAS  Google Scholar 

Download references

Acknowledgements

We thank A.I. den Hollander and H. Kremer for discussions, the University of Washington Center for Ecogenetics and Environmental Health (CEEH) for SNP mapping, C. Hutter for biostatistical advice and C. Beumer, S. van der Velde-Visser, G. Merkx and E. Sehn for expert technical assistance. We thank all the participating families with Joubert syndrome and S. Aysun, P.F. Chance, D. Knutzen and J. Adkins for clinical and technical support. We thank Y. Xiumin (Department of Cell Biology, Max Planck Institute of Biochemistry) for the antibodies to CEP290 and ninein; J. Salisbury (Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine) for the anti-pan-centrin and B.K. Yoder (Department of Cell Biology, University of Alabama at Birmingham Medical Center) for rabbit anti-polaris. This work was supported by grants from the Dutch Kidney Foundation (C04.2112 to N.K. and R.R.), Pro Retina Germany (to R.R.), EVI-GENORET (LSHG-CT-2005 512036 to F.P.M.C. and R.R.), Rotterdamse Vereniging Blindenbelangen (to F.P.M.C. and R.R.), Stichting Blindenhulp (to F.P.M.C. and R.R.), Stichting OOG (to F.P.M.C. and R.R.), Algemene Nederlandse Vereniging ter Voorkoming van Blindheid (to F.P.M.C. and R.R.), Landelijke Stichting voor Blinden en Slechtzienden (to A.K. and F.P.M.C.), FAUN-Stiftung (to U.W.), Forschung contra Blindheit (to T.M. and U.W.), the US National Institutes of Health (grants K23-NS45832 to M.A.P., K24-HD46712 to I.A.G., and K12-RR023265 to D.D., the University of Washington Center on Human Development and Disability (NICHD P30 HD02274 to D.D., M.A.P. and I.A.G.), the University of Washington CEEH, the US National Institute of Environmental Health Sciences (P30ES07033 to F.M.F.) and the March of Dimes Endowment for Healthier Babies at Children's Hospital in Seattle to D.D., M.A.P. and I.A.G.).

Author information

Author notes

  1. Heleen H Arts and Dan Doherty: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Human Genetics, Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, Nijmegen, 6500, HB, The Netherlands

    Heleen H Arts, Sylvia E C van Beersum, Stef J F Letteboer, Krysta Voesenek, Aileen Kartono, Han G Brunner, Frans P M Cremers, Nine V A M Knoers & Ronald Roepman

  2. Department of Pediatrics, University of Washington School of Medicine, Seattle, 98195-6320, Washington, USA

    Dan Doherty, Melissa A Parisi, Nicholas T Gorden & Ian A Glass

  3. Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, Nijmegen, 6500, HB, The Netherlands

    Theo A Peters

  4. Institut für Zoologie, Johannes Gutenberg University, Mainz, D-55099, Germany

    Tina Märker & Uwe Wolfrum

  5. Department of Pediatrics, Ondokuz Mayis University, Kurupelit/Samsun, 55139, Turkey

    Hamit Ozyurek

  6. Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, 98195-7234, Washington, USA

    Federico M Farin

  7. Division of Biomedical Genetics, University Medical Center Utrecht, Utrecht, 3508, AB, The Netherlands

    Hester Y Kroes

Authors
  1. Heleen H Arts
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Dan Doherty
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Sylvia E C van Beersum
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Melissa A Parisi
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Stef J F Letteboer
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Nicholas T Gorden
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Theo A Peters
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Tina Märker
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Krysta Voesenek
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Aileen Kartono
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Hamit Ozyurek
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Federico M Farin
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Hester Y Kroes
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Uwe Wolfrum
    View author publications

    You can also search for this author inPubMed Google Scholar

  15. Han G Brunner
    View author publications

    You can also search for this author inPubMed Google Scholar

  16. Frans P M Cremers
    View author publications

    You can also search for this author inPubMed Google Scholar

  17. Ian A Glass
    View author publications

    You can also search for this author inPubMed Google Scholar

  18. Nine V A M Knoers
    View author publications

    You can also search for this author inPubMed Google Scholar

  19. Ronald Roepman
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

The study was designed by N.V.A.M.K. and R.R., who share senior authorship of this paper. H.H.A., S.E.C.v.B., S.J.F.L., T.A.P., T.M., A.K. and U.W. analyzed protein expression and localization; T.M. and U.W. performed immuno-electron microscopy; H.H.A. and S.J.F.L. analyzed protein-protein interactions; S.E.C.v.B. analyzed gene expression; M.A.P., H.O., H.Y.K. and N.V.A.M.K. acquired clinical data; D.D., N.T.G and F.M.F. performed mapping of microsatellites and SNPs; S.E.C.v.B., N.T.G. and K.V. performed sequence analysis of families; D.D., H.G.B., F.P.M.C., I.A.G., N.V.A.M.K. and R.R. supervised the work and H.H.A., D.D. and R.R. wrote the manuscript, with assistance from most of the coauthors.

Corresponding author

Correspondence to Ronald Roepman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Reciprocal GST pulldown analysis of RPGRIP1L and nephrocystin-4. (PDF 319 kb)

Supplementary Fig. 2

Localization of eCFP-nephrocystin-4 and mRFP-RPGRIP1LC2-N-end in COS-1 cells. (PDF 531 kb)

Supplementary Fig. 3

Confirmation of the specificity of the anti-RPGRIP1L antibody SNC040. (PDF 364 kb)

Supplementary Fig. 4

Confirmation of the specificity of staining by the anti-RPGRIP1L antibody SNC040 in the retina, brain and kidney. (PDF 121 kb)

Supplementary Fig. 5

Localization of RPGRIP1L and nephrocystin-4 in the retina. (PDF 167 kb)

Supplementary Fig. 6

Joubert syndrome–associated mutations in RPGRIP1L disrupt the interaction with nephrocystin-4. (PDF 209 kb)

Supplementary Table 1

Affected individuals with RPGRIP1L mutations show features of Joubert syndrome and Meckel-Gruber syndrome. (PDF 95 kb)

Supplementary Table 2

Oligonucleotide primers used for RT-PCR and sequencing of RPGRIP1L and for RT-PCR of RPGRIP1, NPHP4 and GAPDH. (PDF 87 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Arts, H., Doherty, D., van Beersum, S. 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). https://doi.org/10.1038/ng2069

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng2069

Search

Advanced 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