Department of Medicine, Renal Division, University of Freiburg Medical Center, Freiburg, Germany.
Nat Genet. 2013 Aug;45(8):951-6. doi: 10.1038/ng.2681. Epub 2013 Jun 23.
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.
先天性肾病综合征是一种常染色体隐性遗传性囊性肾病，可导致儿童或青少年肾衰竭。大多数 NPHP 基因产物形成分子网络。在这里，我们确定 ANKS6 为一个新的 NPHP 家族成员，它将 NEK8（NPHP9）连接到 INVS（NPHP2）和 NPHP3。我们证明 ANKS6 定位于近端纤毛，并通过在斑马鱼和非洲爪蟾中的敲低实验证实其在肾脏发育中的作用。我们还鉴定了六个受先天性肾病综合征影响的 ANKS6 突变家族，包括严重的心血管异常、肝纤维化和内脏反位。氧传感器 HIF1AN 使 ANKS6 和 INVS 羟基化，并改变 ANKS6-INVS-NPHP3 模块的组成。在非洲爪蟾中敲低 Hif1an 会导致类似于其他 NPHP 蛋白缺失的表型。网络分析揭示了其他潜在的 NPHP 蛋白，并将 ANKS6 置于该 NPHP 模块的中心，解释了由 ANKS6、NEK8、INVS 或 NPHP3 突变引起的重叠疾病表现。
