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

Nat Genet. 2007 Jul;39(7):882-8. doi: 10.1038/ng2069. Epub 2007 Jun 10.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • NPHP4 protein, human
  • Proteins
  • RPGRIP1 protein, human
  • RPGRIP1L protein, human

Associated data

  • GENBANK/BAA76849
  • RefSeq/NM_015272
  • RefSeq/NP_065099