title: ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3.
abstract: Nephronophthisis is an autosomal recessive cystic kidney disease that leads to renal failure in childhood or adolescence. Most NPHP gene products form molecular networks. Here we identify ANKS6 as a new NPHP family member that connects NEK8 (NPHP9) to INVS (NPHP2) and NPHP3. We show that ANKS6 localizes to the proximal cilium and confirm its role in renal development through knockdown experiments in zebrafish and Xenopus laevis. We also identify six families with ANKS6 mutations affected by nephronophthisis, including severe cardiovascular abnormalities, liver fibrosis and situs inversus. The oxygen sensor HIF1AN hydroxylates ANKS6 and INVS and alters the composition of the ANKS6-INVS-NPHP3 module. Knockdown of Hif1an in Xenopus results in a phenotype that resembles loss of other NPHP proteins. Network analyses uncovered additional putative NPHP proteins and placed ANKS6 at the center of this NPHP module, explaining the overlapping disease manifestation caused by mutation in ANKS6, NEK8, INVS or NPHP3.
authors.affiliation: Department of Medicine, Renal Division, University of Freiburg Medical Center, Freiburg, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Hoff
authors.forename: Jan
authors.initials: J
authors.lastname: Halbritter
authors.forename: Daniel
authors.initials: D
authors.lastname: Epting
authors.forename: Valeska
authors.initials: V
authors.lastname: Frank
authors.forename: Thanh-Minh T
authors.initials: TM
authors.lastname: Nguyen
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Reeuwijk
authors.forename: Christopher
authors.initials: C
authors.lastname: Boehlke
authors.forename: Christoph
authors.initials: C
authors.lastname: Schell
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yasunaga
authors.forename: Martin
authors.initials: M
authors.lastname: Helmstädter
authors.forename: Miriam
authors.initials: M
authors.lastname: Mergen
authors.forename: Emilie
authors.initials: E
authors.lastname: Filhol
authors.forename: Karsten
authors.initials: K
authors.lastname: Boldt
authors.forename: Nicola
authors.initials: N
authors.lastname: Horn
authors.forename: Marius
authors.initials: M
authors.lastname: Ueffing
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.forename: Tobias
authors.initials: T
authors.lastname: Eisenberger
authors.forename: Mariet W
authors.initials: MW
authors.lastname: Elting
authors.forename: Joanna A E
authors.initials: JA
authors.lastname: van Wijk
authors.forename: Detlef
authors.initials: D
authors.lastname: Bockenhauer
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Sebire
authors.forename: Søren
authors.initials: S
authors.lastname: Rittig
authors.forename: Mogens
authors.initials: M
authors.lastname: Vyberg
authors.forename: Troels
authors.initials: T
authors.lastname: Ring
authors.forename: Martin
authors.initials: M
authors.lastname: Pohl
authors.forename: Lars
authors.initials: L
authors.lastname: Pape
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Neuhaus
authors.forename: Neveen A Soliman
authors.initials: NA
authors.lastname: Elshakhs
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Koon
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
authors.forename: Florian
authors.initials: F
authors.lastname: Grahammer
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
authors.forename: E Wolfgang
authors.initials: EW
authors.lastname: Kuehn
authors.forename: Albrecht
authors.initials: A
authors.lastname: Kramer-Zucker
authors.forename: Hanno J
authors.initials: HJ
authors.lastname: Bolz
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.forename: Sophie
authors.initials: S
authors.lastname: Saunier
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.forename: Carsten
authors.initials: C
authors.lastname: Bergmann
authors.forename: Soeren S
authors.initials: SS
authors.lastname: Lienkamp
mesh_terms: D000818:Animals; D002923:Cilia / Q000378:metabolism; D003241:Consanguinity; D005091:Exons; D055785:Gene Knockdown Techniques; D006801:Humans; D007438:Introns; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000378:metabolism; D016547:Kinesins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D000072379:NIMA-Related Kinases; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000235:genetics; D011485:Protein Binding; D060066:Protein Interaction Maps; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014981:Xenopus / Q000196:embryology / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C532258:ANKS6 protein, human; C114503:INVS protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; D011494:Protein Kinases; C458529:NEK8 protein, human; D000072379:NIMA-Related Kinases; C528697:nephrocystin-3, human; D016547:Kinesins