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

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

Research output: Contribution to journalArticleAcademicpeer-review

249 Citations (Scopus)


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). 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.

Original languageEnglish
Pages (from-to)882-888
Number of pages7
JournalNature Genetics
Issue number7
Publication statusPublished - Jul-2007
Externally publishedYes


  • Adaptor Proteins, Signal Transducing/genetics
  • Adult
  • Animals
  • Cell Line
  • Cerebellar Diseases/genetics
  • Cilia/genetics
  • Ciliary Motility Disorders/genetics
  • Eye Diseases/genetics
  • Female
  • Humans
  • Kidney Diseases/genetics
  • Male
  • Molecular Sequence Data
  • Pedigree
  • Proteins/genetics
  • Rats
  • Syndrome

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