Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome.
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.
Arts
Heleen H
HH
Department of Human Genetics, Radboud University Nijmegen Medical Centre and Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands.
Doherty
Dan
D
van Beersum
Sylvia E C
SE
Parisi
Melissa A
MA
Letteboer
Stef J F
SJ
Gorden
Nicholas T
NT
Peters
Theo A
TA
Märker
Tina
T
Voesenek
Krysta
K
Kartono
Aileen
A
Ozyurek
Hamit
H
Farin
Federico M
FM
Kroes
Hester Y
HY
Wolfrum
Uwe
U
Brunner
Han G
HG
Cremers
Frans P M
FP
Glass
Ian A
IA
Knoers
Nine V A M
NV
Roepman
Ronald
R
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D000818:Animals; D002460:Cell Line; D002526:Cerebellar Diseases / Q000235:genetics*; D002923:Cilia / Q000235:genetics*; D002925:Ciliary Motility Disorders / Q000235:genetics*; D003598:Cytoskeletal Proteins; D005128:Eye Diseases / Q000235:genetics*; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D013577:Syndrome
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C491578:NPHP4 protein, human; D011506:Proteins; C415903:RPGRIP1 protein, human; C532826:RPGRIP1L protein, human