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XB-ART-47285
Nat Genet August 1, 2013; 45 (8): 951-6.
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ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3.

Hoff S , Halbritter J , Epting D , Frank V , Nguyen TM , van Reeuwijk J , Boehlke C , Schell C , Yasunaga T , Helmstädter M , Mergen M , Filhol E , Boldt K , Horn N , Ueffing M , Otto EA , Eisenberger T , Elting MW , van Wijk JA , Bockenhauer D , Sebire NJ , Rittig S , Vyberg M , Ring T , Pohl M , Pape L , Neuhaus TJ , Elshakhs NA , Koon SJ , Harris PC , Grahammer F , Huber TB , Kuehn EW , Kramer-Zucker A , Bolz HJ , Roepman R , Saunier S , Walz G , Hildebrandt F , Bergmann C , Lienkamp SS .


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.

PubMed ID: 23793029
PMC ID: PMC3786259
Article link: Nat Genet
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: ank1 ankrd6 anks6 atp1a1 atp1b1 bicc1 cd2ap dnai1 hif1an invs lhx1 nek8 nphp1 nphp3 odc1 slc12a1 slc4a4 slc5a1.2
GO keywords: kidney development
Morpholinos: anks6 MO1 hif1an MO1 nek8 MO1

Disease Ontology terms: nephronophthisis [+]
OMIMs: NEPHRONOPHTHISIS 16; NPHP16
Phenotypes: Xla Wt + hif1an MO (Fig 4d)

Article Images: [+] show captions
References [+] :
Benzing, Clinical spectrum and pathogenesis of nephronophthisis. 2012, Pubmed