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

Authors:
  • DDDan Doherty
    Dan Doherty
  • SBSylvia E C van Beersum
    Sylvia E C van Beersum
  • MPMelissa A Parisi
    Melissa A Parisi
  • SLStef J F Letteboer
    Stef J F Letteboer
  • NGNicholas T Gorden
    Nicholas T Gorden
  • TMTina Märker
    Tina Märker
  • KVKrysta Voesenek
    Krysta Voesenek
  • AKAileen Kartono
    Aileen Kartono
  • HOHamit Ozyurek
    Hamit Ozyurek
  • FFFederico M Farin
    Federico M Farin
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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-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.

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