The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4.
The molecular basis of nephronophthisis, the most frequent genetic cause of renal failure in children and young adults, and its association with retinal degeneration and cerebellar vermis aplasia in Joubert syndrome are poorly understood. Using positional cloning, we here identify mutations in the gene CEP290 as causing nephronophthisis. It encodes a protein with several domains also present in CENPF, a protein involved in chromosome segregation. CEP290 (also known as NPHP6) interacts with and modulates the activity of ATF4, a transcription factor implicated in cAMP-dependent renal cyst formation. NPHP6 is found at centrosomes and in the nucleus of renal epithelial cells in a cell cycle-dependent manner and in connecting cilia of photoreceptors. Abrogation of its function in zebrafish recapitulates the renal, retinal and cerebellar phenotypes of Joubert syndrome. Our findings help establish the link between centrosome function, tissue architecture and transcriptional control in the pathogenesis of cystic kidney disease, retinal degeneration, and central nervous system development.
Sayer
John A
JA
Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Otto
Edgar A
EA
O'Toole
John F
JF
Nurnberg
Gudrun
G
Kennedy
Michael A
MA
Becker
Christian
C
Hennies
Hans Christian
HC
Helou
Juliana
J
Attanasio
Massimo
M
Fausett
Blake V
BV
Utsch
Boris
B
Khanna
Hemant
H
Liu
Yan
Y
Drummond
Iain
I
Kawakami
Isao
I
Kusakabe
Takehiro
T
Tsuda
Motoyuki
M
Ma
Li
L
Lee
Hwankyu
H
Larson
Ronald G
RG
Allen
Susan J
SJ
Wilkinson
Christopher J
CJ
Nigg
Erich A
EA
Shou
Chengchao
C
Lillo
Concepcion
C
Williams
David S
DS
Hoppe
Bernd
B
Kemper
Markus J
MJ
Neuhaus
Thomas
T
Parisi
Melissa A
MA
Glass
Ian A
IA
Petry
Marianne
M
Kispert
Andreas
A
Gloy
Joachim
J
Ganner
Athina
A
Walz
Gerd
G
Zhu
Xueliang
X
Goldman
Daniel
D
Nurnberg
Peter
P
Swaroop
Anand
A
Leroux
Michel R
MR
Hildebrandt
Friedhelm
F