Abstract

Despite rapid advances in the identification of genes involved in disease, the predictive power of the genotype remains limited, in part owing to poorly understood effects of second-site modifiers. Here we demonstrate that a polymorphic coding variant of RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein-1 like), a ciliary gene mutated in Meckel-Gruber (MKS) and Joubert (JBTS) syndromes, is associated with the development of retinal degeneration in individuals with ciliopathies caused by mutations in other genes. As part of our resequencing efforts of the ciliary proteome, we identified several putative loss-of-function RPGRIP1L mutations, including one common variant, A229T. Multiple genetic lines of evidence showed this allele to be associated with photoreceptor loss in ciliopathies. Moreover, we show that RPGRIP1L interacts biochemically with RPGR, loss of which causes retinal degeneration, and that the Thr229-encoded protein significantly compromises this interaction. Our data represent an example of modification of a discrete phenotype of syndromic disease and highlight the importance of a multifaceted approach for the discovery of modifier alleles of intermediate frequency and effect.

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Acknowledgements

We thank the individuals affected with ciliopathies and their families for their continued support and encouragement. We also thank H. Arts for critical evaluation of the manuscript. This work was supported by grants R01EY007961 from the National Eye Institute (H.K. and A.S.), R01HD04260 from the National Institute of Child Health and Development (N.K.), R01DK072301, R01DK075972 (N.K.), R01DK068306, R01DK064614, R01DK069274 (F.H.), NRSA fellowship F32 DK079541 (E.E.D.) from the National Institute of Diabetes, Digestive and Kidney disorders, Intramural program of NEI (A.S.), the Macular Vision Research Foundation (N.K.), the Foundation for Fighting Blindness (H.K., S.S.B., A.S. and N.K.), the Foundation for Fighting Blindness Canada (R.K.K.), Le Fonds de la recherche en sante du Québec (FRSQ) (R.K.K.), Research to Prevent Blindness (A.S.), Harold Falls Collegiate Professorship (A.S.), the Midwest Eye Banks and Transplantation Center (H.K.), the Searle Scholars Program (M.A.B.), the Deutsche Forschungsgemeinschaft (DFG grant BE 3910/4-1; C.B.) the UK Medical Research Council (grant number G0700073; C.A.J.), NIHR Biomedical Research Centre for Ophthalmology (S.S.B.) and EU-GENORET Grant LSHG-CT-2005-512036 (S.S.B.). F.H. is an investigator of the Howard Hughes Medical Institute (HHMI) and a Doris Duke Distinguished Clinical Scientist (DDCF).

Author information

Author notes

    • Hemant Khanna
    •  & Erica E Davis

    These authors contributed equally to this work.

Affiliations

  1. Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, USA.

    • Hemant Khanna
    • , Carlos A Murga-Zamalloa
    • , Alejandro Estrada-Cuzcano
    • , Mohammad I Othman
    •  & Anand Swaroop
  2. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Erica E Davis
    • , Perciliz L Tan
    • , Michael A Beer
    •  & Nicholas Katsanis
  3. McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, Quebec, Canada.

    • Irma Lopez
    •  & Robert K Koenekoop
  4. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Anneke I den Hollander
    •  & Marijke N Zonneveld
  5. Institute of Ophthalmology, University College London, London, UK.

    • Naushin Waseem
    • , Christina F Chakarova
    • , Cecilia Maubaret
    •  & Shomi S Bhattacharya
  6. Molecular Medicine Unit, Institute of Child Health, University College London, London, UK.

    • Anna Diaz-Font
    •  & Philip L Beales
  7. Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, Maryland, USA.

    • Ian MacDonald
  8. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.

    • Donna M Muzny
    • , David A Wheeler
    • , Margaret Morgan
    • , Lora R Lewis
    •  & Richard A Gibbs
  9. Section of Ophthalmology and Neurosciences, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, UK.

    • Clare V Logan
    • , Chris F Inglehearn
    •  & Colin A Johnson
  10. Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Michael A Beer
  11. Departments of Ophthalmology, Baylor College of Medicine, Houston, Texas, USA.

    • Richard A Lewis
  12. Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

    • Richard A Lewis
  13. Pediatrics, Baylor College of Medicine, Houston, Texas, USA.

    • Richard A Lewis
  14. Medicine, Baylor College of Medicine, Houston, Texas, USA.

    • Richard A Lewis
  15. Scheie Eye Institute, Department of Ophthalmology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Samuel G Jacobson
  16. Department of Human Genetics, RWTH University of Aachen, Aachen, Germany.

    • Carsten Bergmann
  17. Département de Génétique et INSERM U-781, Hôpital Necker-Enfants Malades, Paris, France.

    • Tania Attié-Bitach
  18. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.

    • Edgar A Otto
    • , Friedhelm Hildebrandt
    •  & Anand Swaroop
  19. Howard Hughes Medical Institute and Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.

    • Friedhelm Hildebrandt
  20. Neurobiology Neurodegeneration and Repair Laboratory, National Eye Institute, Bethesda, Maryland, USA.

    • Anand Swaroop
  21. Wilmer Eye Institute and Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Nicholas Katsanis

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Contributions

H.K., E.E.D., A.S. and N.K. designed experiments and analyzed data; H.K., E.E.D., C.A.M.-Z., A.E.-C., I.L., A.I.d.H., M.N.Z., M.I.O., N.W., C.F.C., C.M., A.D.-F., C.V.L. and P.L.T. performed experiments; M.A.B. performed permutation analysis; C.F.I., R.A.L., S.G.J., C.B., P.L.B., T.A.-B., C.A.J., E.A.O., S.S.B., F.H. and R.K.K. provided subject DNA, genotypes, or clinical information; D.M.M., D.A.W., M.M., L.R.L. and R.A.G. generated and analyzed medical resequencing data; H.K., E.E.D., A.S. and N.K. wrote the manuscript.

Corresponding authors

Correspondence to Anand Swaroop or Nicholas Katsanis.

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DOI

https://doi.org/10.1038/ng.366

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