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

ZMYM2突变的疾病机制是肾脏和泌尿道先天性异常的新单基因原因

• 批准号: 442070894
• 负责人: Dr. Steve Seltzsam
• 金额: --
• 依托单位: Division of Nephrology
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/442070894?language=en
• 关键词: Disease; mechanisms; ZMYM2; mutations; new

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.

先天性肾脏和泌尿道异常（CAKUT）是一组异质性疾病，是25岁以下患者慢性肾脏疾病的最常见原因。发病机制是由受损的胚胎肾脏和泌尿道发育驱动的。虽然大多数CAKUT病例的致病机制尚未解决，但最近的研究表明，一些表型是由于在肾发生中起基本作用的基因中的单基因突变引起的。通过全外显子组测序（WES）在大型国际队列的CAKUT受影响的个人，44个单基因基因CAKUT的原因，可以发现到目前为止，从而解开信号通路在肾脏和泌尿道的发展。最近，在宿主实验室中发现了MYM型锌指2型（ZMYM 2）基因突变，代表了具有严重肾外表型的CAKUT的一种新的单基因原因。尽管ZMYM 2截短突变的病理生理学可能与蛋白质核易位的废除有关，特别是错义突变的疾病机制仍然难以捉摸。该项目将重点关注CAKUT的新单基因原因的发现和ZMYM 2错义突变的致病机制的描绘。因此，将使用细胞培养模型来研究用取自CAKUT受影响患者的相应突变转染后的蛋白质-蛋白质相互作用配偶体和转录活性。将使用发育中的小鼠肾脏研究可能的相互作用伙伴的作用。WES将应用于一个大型的CAKUT受影响家庭的国际队列，以绘制突变景观并找到新的致病单基因。总之，该项目将为CAKUT的疾病机制提供额外的证据，从而对潜在的发展途径有一个基本的了解。

项目成果

Whole exome sequencing identifies FOXL2, FOXA2 and FOXA3 as candidate genes for monogenic congenital anomalies of the kidneys and urinary tract.

全外显子组测序将 FOXL2、FOXA2 和 FOXA3 确定为肾脏和泌尿道单基因先天性异常的候选基因

• DOI: 10.1093/ndt/gfab253
• 发表时间: 2021
• 期刊: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
• 作者: Zheng B;Seltzsam S;Wang C;Schierbaum L;Schneider S;Connaughton DM;Nakayama M;Mann N;Stajic N;Mane S;Bauer SB;Tasic V;Nam HJ;Shril S;Hildebrandt F
• 通讯作者: Hildebrandt F

A truncating NRIP1 variant in an Arabic family with congenital anomalies of the kidneys and urinary tract.

阿拉伯家庭中的 NRIP1 截短变体，患有先天性肾脏和泌尿道异常。

• DOI: 10.1002/ajmg.a.62502
• 发表时间: 2022
• 期刊: American journal of medical genetics. Part A
• 作者: Zheng,Bixia;Wang,Chunyan;Seltzsam,Steve;Schneider,Sophia;Schierbaum,Luca;Wu,Wilfred;Dai,Rufeng;Connaughton,DervlaM;Nakayama,Makiko;Mann,Nina;Bauer,StuartB;Awad,HazemS;Eid,LoaiA;Tasic,Velibor;Shril,Shirlee;Hildebrandt,Fri
• 通讯作者: Hildebrandt,Fri