Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.

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.

Screen for multi-SUMO-binding proteins reveals a multi-SIM-binding mechanism for recruitment of the transcriptional regulator ZMYM2 to chromatin.

Protein SUMOylation has emerged as an important regulatory event, particularly in nuclear processes such as transcriptional control and DNA repair. In this context, small ubiquitin-like modifier (SUMO) often provides a binding platform for the recruitment of proteins via their SUMO-interacting motifs (SIMs). Recent discoveries point to an important role for multivalent SUMO binding through multiple SIMs in the binding partner as exemplified by poly-SUMOylation acting as a binding platform for ubiquitin E3 ligases such as ring finger protein 4. Here, we have investigated whether other types of protein are recruited through multivalent SUMO interactions. We have identified dozens of proteins that bind to multi-SUMO platforms, thereby uncovering a complex potential regulatory network. Multi-SUMO binding is mediated through multi-SIM modules, and the functional importance of these interactions is demonstrated for the transcriptional corepressor ZMYM2/ZNF198 where its multi-SUMO-binding activity is required for its recruitment to chromatin.