title: Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy.
abstract: 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.
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.forename: Toby W
authors.initials: TW
authors.lastname: Hurd
authors.forename: Rannar
authors.initials: R
authors.lastname: Airik
authors.forename: Moumita
authors.initials: M
authors.lastname: Chaki
authors.forename: Weibin
authors.initials: W
authors.lastname: Zhou
authors.forename: Corinne
authors.initials: C
authors.lastname: Stoetzel
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Patil
authors.forename: Shawn
authors.initials: S
authors.lastname: Levy
authors.forename: Amiya K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Murga-Zamalloa
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Reeuwijk
authors.forename: Stef J F
authors.initials: SJ
authors.lastname: Letteboer
authors.forename: Liyun
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authors.lastname: Sang
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Giles
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.forename: Karlien L M
authors.initials: KL
authors.lastname: Coene
authors.forename: Alejandro
authors.initials: A
authors.lastname: Estrada-Cuzcano
authors.forename: Rob W J
authors.initials: RW
authors.lastname: Collin
authors.forename: Heather M
authors.initials: HM
authors.lastname: McLaughlin
authors.forename: Susanne
authors.initials: S
authors.lastname: Held
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Kasanuki
authors.forename: Gokul
authors.initials: G
authors.lastname: Ramaswami
authors.forename: Jinny
authors.initials: J
authors.lastname: Conte
authors.forename: Irma
authors.initials: I
authors.lastname: Lopez
authors.forename: Joseph
authors.initials: J
authors.lastname: Washburn
authors.forename: James
authors.initials: J
authors.lastname: Macdonald
authors.forename: Jinghua
authors.initials: J
authors.lastname: Hu
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Guay-Woodford
authors.forename: Hartmut P H
authors.initials: HP
authors.lastname: Neumann
authors.forename: Nicholas
authors.initials: N
authors.lastname: Obermüller
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
authors.forename: Carsten
authors.initials: C
authors.lastname: Bergmann
authors.forename: Xiaoshu
authors.initials: X
authors.lastname: Bei
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lewis
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: Vanda
authors.initials: V
authors.lastname: Lopes
authors.forename: David S
authors.initials: DS
authors.lastname: Williams
authors.forename: Robert H
authors.initials: RH
authors.lastname: Lyons
authors.forename: Chi V
authors.initials: CV
authors.lastname: Dang
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Brito
authors.forename: Mónica Bettencourt
authors.initials: MB
authors.lastname: Dias
authors.forename: Xinmin
authors.initials: X
authors.lastname: Zhang
authors.forename: James D
authors.initials: JD
authors.lastname: Cavalcoli
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Eric A
authors.initials: EA
authors.lastname: Pierce
authors.forename: Peter K
authors.initials: PK
authors.lastname: Jackson
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
authors.forename: Sophie
authors.initials: S
authors.lastname: Saunier
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.forename: Helene
authors.initials: H
authors.lastname: Dollfus
authors.forename: Hemant
authors.initials: H
authors.lastname: Khanna
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: 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
chemical_list: 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