Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.

先天性肾脏和尿路异常 (CAKUT) 是最常见的出生缺陷之一，也是生命前三十年慢性肾脏疾病的最常见原因。尽管发现了数十种 CAKUT 的单基因原因，但大多数致病途径仍然难以捉摸。我们对 551 名患有 CAKUT 的个体进行了全外显子组测序 (WES)，并在两个不同的 CAKUT 家族中鉴定出了ZMYM2杂合的de novo stop-gain 变异。通过合作，我们在 15 个不相关的家族中总共鉴定出了ZMYM2的 14 个不同的杂合功能丧失突变。大多数突变是从头发生的，表明可能干扰生殖功能。人类疾病特征在吗啉代敲低的热带X.幼虫中得到复制，其中基于个体突变的截短 ZMYM2 蛋白的表达未能挽救肾脏和颅面缺陷。此外，杂合子 Zmym2 缺陷小鼠以高外显率重现了 CAKUT 的特征。 ZMYM2 蛋白是转录辅阻遏物复合物的一个组成部分，最近与发育调节的内源性逆转录病毒元件的沉默相关。通过蛋白质-蛋白质相互作用测定，我们发现 ZMYM2 与其他表观遗传沉默复合物相互作用，并证实它与 FOXP1 结合，FOXP1 是一种也与 CAKUT 相关的转录因子。总之，我们的研究结果证实， ZMYM2的功能丧失突变以及其相互作用组中其他蛋白质的功能丧失突变可能是人类 CAKUT 的原因，为研究该疾病的发病机制提供了新途径。