Letter abstract


Nature Genetics 41, 739 - 745 (2009)
Published online: 10 May 2009 | doi:10.1038/ng.366

A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies

Hemant Khanna1,22, Erica E Davis2,22, Carlos A Murga-Zamalloa1, Alejandro Estrada-Cuzcano1, Irma Lopez3, Anneke I den Hollander4, Marijke N Zonneveld4, Mohammad I Othman1, Naushin Waseem5, Christina F Chakarova5, Cecilia Maubaret5, Anna Diaz-Font6, Ian MacDonald7, Donna M Muzny8, David A Wheeler8, Margaret Morgan8, Lora R Lewis8, Clare V Logan9, Perciliz L Tan2, Michael A Beer2,10, Chris F Inglehearn9, Richard A Lewis11,12,13,14, Samuel G Jacobson15, Carsten Bergmann16, Philip L Beales6, Tania Attié-Bitach17, Colin A Johnson9, Edgar A Otto18, Shomi S Bhattacharya5, Friedhelm Hildebrandt18,19, Richard A Gibbs8, Robert K Koenekoop3, Anand Swaroop1,18,20 & Nicholas Katsanis2,21

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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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  1. Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, USA.
  2. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  3. McGill Ocular Genetics Laboratory, McGill University Health Centre, Montreal, Quebec, Canada.
  4. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
  5. Institute of Ophthalmology, University College London, London, UK.
  6. Molecular Medicine Unit, Institute of Child Health, University College London, London, UK.
  7. Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Bethesda, Maryland, USA.
  8. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
  9. Section of Ophthalmology and Neurosciences, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, UK.
  10. Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  11. Departments of Ophthalmology, Baylor College of Medicine, Houston, Texas, USA.
  12. Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
  13. Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
  14. Medicine, Baylor College of Medicine, Houston, Texas, USA.
  15. Scheie Eye Institute, Department of Ophthalmology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  16. Department of Human Genetics, RWTH University of Aachen, Aachen, Germany.
  17. Département de Génétique et INSERM U-781, Hôpital Necker-Enfants Malades, Paris, France.
  18. Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
  19. Howard Hughes Medical Institute and Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
  20. Neurobiology Neurodegeneration and Repair Laboratory, National Eye Institute, Bethesda, Maryland, USA.
  21. Wilmer Eye Institute and Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
  22. These authors contributed equally to this work.

Correspondence to: Anand Swaroop1,18,20 e-mail: swaroopa@nei.nih.gov

Correspondence to: Nicholas Katsanis2,21 e-mail: katsanis@jhmi.edu



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