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

点击翻译按钮获取中文摘要

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.