ANKS6 is a central component of a nephronophthisis module linking NEK8 to INVS and NPHP3

作者：Hoff Sylvia; Halbritter Jan; Epting Daniel; Frank Valeska; Nguyen Thanh Minh T; van Reeuwijk Jeroen; Boehlke Christopher; Schell Christoph; Yasunaga Takayuki; Helmstaedter Martin; Mergen Miriam; Filhol Emilie; Boldt Karsten; Horn Nicola; Ueffing Marius; Otto Edgar A; Eisenberger Tobias; Elting Mariet W; van Wijk Joanna A E; Bockenhauer Detlef; Sebire Neil J; Rittig Soren; Vyberg Mogens; Ring Troels; Pohl Martin; Pape Lars; Neuhaus Thomas J

来源：Nature Genetics, 2013, 45(8): 951-U160.

DOI：10.1038/ng.2681

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.

• 出版日期2013-8