4.8 Article

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

Journal

NATURE GENETICS
Volume 39, Issue 7, Pages 882-888

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/ng2069

Keywords

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Funding

  1. NCRR NIH HHS [K12-RR023265] Funding Source: Medline
  2. NICHD NIH HHS [P30 HD02274, K24-HD46712] Funding Source: Medline
  3. NIEHS NIH HHS [P30ES07033] Funding Source: Medline
  4. NINDS NIH HHS [K23-NS45832] Funding Source: Medline

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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)(1-6). 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 amaurosis(7,8). 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.

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