Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction. Here, we describe mutations in DZIP1L, which encodes DAZ interacting protein 1-like, in patients with ARPKD. We further validated these findings through loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and to the distal ends of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone. In agreement with a defect in the diffusion barrier, we found that the ciliary-membrane translocation of the PKD proteins polycystin-1 and polycystin-2 is compromised in DZIP1L-mutant cells. Together, these data provide what is, to our knowledge, the first conclusive evidence that ARPKD is not a homogeneous disorder and further establish DZIP1L as a second gene involved in ARPKD pathogenesis.

中文翻译：

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DZIP1L中的突变，其编码睫状过渡区蛋白，导致常染色体隐性隐性多囊肾疾病

常染色体隐性隐性多囊肾疾病（ARPKD）通常被认为是由PKHD1突变引起的遗传同质性疾病，已与睫状功能障碍相关。在这里，我们描述了ARPKD患者中DZIP1L中的突变，该突变编码DAZ相互作用蛋白1样。我们通过在小鼠和斑马鱼中进行的功能丧失研究进一步验证了这些发现。DZIP1L定位于中心细胞和基体的远端，并与septin2相互作用，该蛋白与在睫状过渡区的睫状体弥散屏障的维持有关。与扩散障碍中的缺陷相一致，我们发现DZIP1L中PKD蛋白polycystin-1和polycystin-2的睫状膜移位受到损害-突变细胞。这些数据一起提供了我们所知的第一个确凿证据，表明ARPKD不是同质性疾病，并进一步将DZIP1L确立为涉及ARPKD发病机理的第二个基因。