Cerebello-oculo-renal syndrome (CORS), also called Joubert syndrome type B, and Meckel (MKS) syndrome belong to the group of developmental autosomal recessive disorders that are associated with primary cilium dysfunction. Using SNP mapping, we identified missense and truncating mutations in RPGRIP1L (KIAA1005) in both CORS and MKS, and we show that inactivation of the mouse ortholog Rpgrip1l (Ftm) recapitulates the cerebral, renal and hepatic defects of CORS and MKS. In addition, we show that RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4, known genes associated with MKS, CORS and nephronophthisis (a related renal disorder and ciliopathy). In addition, the RPGRIP1L missense mutations found in CORS individuals diminishes the interaction between RPGRIP1L and nephrocystin-4. Our findings show that mutations in RPGRIP1L can cause the multiorgan phenotypic abnormalities found in CORS or MKS, which therefore represent a continuum of the same underlying disorder.

1. Institut National de la Santé et de la Recherche Médicale (INSERM) U-574, Hôpital Necker-Enfants Malades, 75015 Paris, France.
2. Université Paris Descartes, 75006 Paris, France.
3. INSERM U-781, Hôpital Necker-Enfants Malades, 75015 Paris, France.
4. Pediatric Nephrology, Hôpital Necker-Enfants Malades, Assistance Publique–Hôpitaux de Paris (AP-HP), 75015 Paris, France.
5. Centre National de la Recherche Scientifique (CNRS) UMR7622, Laboratoire de Biologie du Développement, 75005 Paris, France.
6. Université Pierre et Marie Curie, 75005 Paris, France.
7. Institut für Entwicklungs und Molekularbiologie der Tiere (EMT), Heinrich-Heine-Universität, 40225 Düsseldorf, Germany.
8. Department of Genetics, Hôpital Necker-Enfants Malades, AP-HP, 75015 Paris, France.
9. West Midlands Regional Genetics, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
10. Departments of Pediatrics and of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
11. Pediatric Radiology, Hôpital Necker-Enfants Malades, AP-HP, 75015 Paris, France.
12. Department of Foetopathology, Hôpital Trousseau, AP-HP, 75012 Paris, France.
13. Department of Pediatric Nephrology, Hôpital Robert Debré, AP-HP, 75019 Paris, France.
14. Department of Nephrology and Clinical Immunology, Centre Hospitalier Universitaire (CHU) Bretonneau, 37000 Tours, France.
15. Department of Pediatric Nephrology, CHU Angers, 49100 Angers, France.
16. Centre de Perharidy, 29680 Roscoff, France.
17. Section of Ophthalmology and Neuroscience, Wellcome Trust Brenner Building, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds LS9 7TF, UK.

Correspondence to: Sophie Saunier^1,2 e-mail: saunier@necker.fr

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