Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome.
Nat Genet
; 39(7): 882-8, 2007 Jul.
Article
in En
| MEDLINE
| ID: mdl-17558407
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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Database:
MEDLINE
Main subject:
Proteins
/
Cerebellar Diseases
/
Cilia
/
Ciliary Motility Disorders
/
Adaptor Proteins, Signal Transducing
/
Eye Diseases
/
Kidney Diseases
Type of study:
Prognostic_studies
Limits:
Adult
/
Animals
/
Female
/
Humans
/
Male
Language:
En
Year:
2007
Type:
Article