Letter abstract
Nature Genetics 39, 882 - 888 (2007)
Published online: 10 June 2007 | doi:10.1038/ng2069
Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome
Heleen H Arts1,8, Dan Doherty2,8, Sylvia E C van Beersum1, Melissa A Parisi2, Stef J F Letteboer1, Nicholas T Gorden2, Theo A Peters3, Tina Märker4, Krysta Voesenek1, Aileen Kartono1, Hamit Ozyurek5, Federico M Farin6, Hester Y Kroes7, Uwe Wolfrum4, Han G Brunner1, Frans P M Cremers1, Ian A Glass2, Nine V A M Knoers1 & Ronald Roepman1
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.
- Department of Human Genetics, Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands.
- Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington 98195-6320, USA.
- Department of Otorhinolaryngology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.
- Institut für Zoologie, Johannes Gutenberg University, D-55099 Mainz, Germany.
- Department of Pediatrics, Ondokuz Mayis University, 55139 Kurupelit/Samsun, Turkey.
- Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, Seattle, Washington 98195-7234, USA.
- Division of Biomedical Genetics, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands.
- These authors contributed equally to this work.
Correspondence to: Ronald Roepman1 e-mail: r.roepman@antrg.umcn.nl
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