Disease mechanisms of ZMYM2 mutations, a new monogenic cause for congenital anomalies of the kidney and urinary tract

先天性肾脏和尿路异常（先天性肾脏和尿路异常）是一组异质性的医疗条件，代表了25岁之前慢性肾脏疾病患者最常见的原因。发病机制是由胚胎肾脏和泌尿道发育受损引起的。尽管大多数CAKUT病例的致病机制尚不清楚，但最近的研究表明，一些表型是由于在肾脏发生中起基本作用的基因的单基因突变引起的。通过全外显子组测序（WES）在大型国际CAKUT患者队列中发现了44个CAKUT单基因病因，从而揭示了肾脏和尿路发育中的信号通路。最近，在宿主实验室中发现了基因mym型锌指2型（ZMYM2）的突变，代表了具有严重肾外表型的CAKUT的一种新的单基因原因。虽然ZMYM2截短突变的病理生理可能与该蛋白核易位的取消有关，但特别是错义突变的疾病机制仍然难以捉摸。本项目将重点发现CAKUT的新的单基因原因，并描述ZMYM2错义突变的致病机制。因此，细胞培养模型将用于研究从受cakut影响的患者中提取的相应突变转染后的蛋白质-蛋白质相互作用伙伴和转录活性。可能的相互作用伙伴的作用将通过发育中的小鼠肾脏进行研究。WES将应用于cakut影响家庭的大型国际队列，以绘制突变景观并发现新的致病单基因。综上所述，该项目将为CAKUT的疾病机制提供更多证据，从而对潜在的发育途径有一个基本的了解。

Congenital anomalies of the kidney and urinary tract (CAKUT) is a heterogenous group of medical conditions representing the most common cause for chronic kidney disease in patients before the age of 25. The pathogenesis is driven by an impaired embryonic kidney and urinary tract development. Although the pathogenic mechanisms of most cases of CAKUT are not yet solved, recent research generated evidence that some phenotypes are due to monogenic mutations in genes that play a fundamental role in nephrogenesis. By Whole Exome Sequencing (WES) in large international cohorts of CAKUT-affected individuals, 44 monogenic gene causes for CAKUT could be found to date, thus unraveling signaling pathways in renal and urinary tract development. Recently, mutations in the gene MYM-type zinc fingers type 2 (ZMYM2) have been discovered in the host laboratory to represent a novel monogenic cause for CAKUT with a severe extrarenal phenotype. Although the pathophysiology of ZMYM2 truncating mutations is possibly linked to an abrogation of nuclear translocation of the protein, especially the disease mechanisms of missense mutations remain elusive. This project will focus on the discovery of new monogenic causes of CAKUT and delineation of the pathogenic mechanisms of ZMYM2 missense mutations. Therefore, a cell culture model will be used to investigate protein-protein interaction partners and transcriptional activity after transfection with corresponding mutations taken from CAKUT-affected patients. The role of possible interaction partners will be investigated using developing mouse kidneys. WES will be applied on a large international cohort of CAKUT-affected families to map the mutational landscape and find new causative monogenic genes. Taken together, this project will provide additional evidence on the disease mechanisms of CAKUT and so give a fundamental understanding of the underlying developmental pathways.