Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy.
Nephronophthisis-related ciliopathies (NPHP-RC) are recessive disorders that feature dysplasia or degeneration occurring preferentially in the kidney, retina and cerebellum. Here we combined homozygosity mapping with candidate gene analysis by performing 'ciliopathy candidate exome capture' followed by massively parallel sequencing. We identified 12 different truncating mutations of SDCCAG8 (serologically defined colon cancer antigen 8, also known as CCCAP) in 10 families affected by NPHP-RC. We show that SDCCAG8 is localized at both centrioles and interacts directly with OFD1 (oral-facial-digital syndrome 1), which is associated with NPHP-RC. Depletion of sdccag8 causes kidney cysts and a body axis defect in zebrafish and induces cell polarity defects in three-dimensional renal cell cultures. This work identifies loss of SDCCAG8 function as a cause of a retinal-renal ciliopathy and validates exome capture analysis for broadly heterogeneous single-gene disorders.
Otto
Edgar A
EA
Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
Hurd
Toby W
TW
Airik
Rannar
R
Chaki
Moumita
M
Zhou
Weibin
W
Stoetzel
Corinne
C
Patil
Suresh B
SB
Levy
Shawn
S
Ghosh
Amiya K
AK
Murga-Zamalloa
Carlos A
CA
van Reeuwijk
Jeroen
J
Letteboer
Stef J F
SJ
Sang
Liyun
L
Giles
Rachel H
RH
Liu
Qin
Q
Coene
Karlien L M
KL
Estrada-Cuzcano
Alejandro
A
Collin
Rob W J
RW
McLaughlin
Heather M
HM
Held
Susanne
S
Kasanuki
Jennifer M
JM
Ramaswami
Gokul
G
Conte
Jinny
J
Lopez
Irma
I
Washburn
Joseph
J
Macdonald
James
J
Hu
Jinghua
J
Yamashita
Yukiko
Y
Maher
Eamonn R
ER
Guay-Woodford
Lisa M
LM
Neumann
Hartmut P H
HP
Obermüller
Nicholas
N
Koenekoop
Robert K
RK
Bergmann
Carsten
C
Bei
Xiaoshu
X
Lewis
Richard A
RA
Katsanis
Nicholas
N
Lopes
Vanda
V
Williams
David S
DS
Lyons
Robert H
RH
Dang
Chi V
CV
Brito
Daniela A
DA
Dias
Mónica Bettencourt
MB
Zhang
Xinmin
X
Cavalcoli
James D
JD
Nürnberg
Gudrun
G
Nürnberg
Peter
P
Pierce
Eric A
EA
Jackson
Peter K
PK
Antignac
Corinne
C
Saunier
Sophie
S
Roepman
Ronald
R
Dollfus
Helene
H
Khanna
Hemant
H
Hildebrandt
Friedhelm
F
D000818:Animals; D001324:Autoantigens / Q000235:genetics*; D015153:Blotting, Western; D016022:Case-Control Studies; D018385:Centrosome / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D005091:Exons / Q000235:genetics*; D005190:Family; D019084:Fluorescent Antibody Technique, Indirect; D018507:Gene Expression Regulation, Developmental; D056726:Genetic Association Studies; D006720:Homozygote; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism / Q000648:ultrastructure; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D012164:Retinal Diseases / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013347:Subcellular Fractions; D020798:Two-Hybrid System Techniques; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development
D001324:Autoantigens; D009363:Neoplasm Proteins; C115130:OFD1 protein, human; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C472380:SDCCAG8 protein, human; D000242:Cyclic AMP