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

Authors: Arts, Heleen H; Doherty, Dan; van Beersum, Sylvia E C; Parisi, Melissa A; Letteboer, Stef J F; Gorden, Nicholas T; Peters, Theo A; Marker, Tina; Voesenek, Krysta; Kartono, Aileen; Ozyurek, Hamit; Farin, Federico M; Kroes, Hester Y; Wolfrum, Uwe; Brunner, Han G; Cremers, Frans P M; Glass, Ian A; Knoers, Nine V A M; Roepman, Ronald

Published In Nat Genet, (2007 Jul)

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-Loken syndrome (SLSN) or Joubert syndrome (JBTS). 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 amaurosis. 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.

PubMed ID: 17558407

MeSH Terms: No MeSH terms associated with this publication