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

TitleMutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.
Publication TypeJournal Article
Year of Publication2020
AuthorsConnaughton, DM, Dai, R, Owen, DJ, Marquez, J, Mann, N, GrAHm-Paquin, AL, Nakayama, M, Coyaud, E, Laurent, EMN, St-Germain, JR, Blok, LSnijders, Vino, A, Klämbt, V, Deutsch, K, Wu, C-HWilfred, Kolvenbach, CM, Kause, F, Ottlewski, I, Schneider, R, Kitzler, TM, Majmundar, AJ, Buerger, F, Onuchic-Whitford, AC, Youying, M, Kolb, A, Salmanullah, D, Chen, E, van der Ven, AT, Rao, J, Ityel, H, Seltzsam, S, Rieke, JM, Chen, J, Vivante, A, Hwang, D-Y, Kohl, S, Dworschak, GC, Hermle, T, Alders, M, Bartolomaeus, T, Bauer, SB, Baum, MA, Brilstra, EH, Challman, TD, Zyskind, J, Costin, CE, Dipple, KM, Duijkers, FA, Ferguson, M, FitzPatrick, DR, Fick, R, Glass, IA, Hulick, PJ, Kline, AD, Krey, I, Kumar, S, Lu, W, Marco, EJ, Wentzensen, IM, Mefford, HC, Platzer, K, Povolotskaya, IS, Savatt, JM, Shcherbakova, NV, Senguttuvan, P, Squire, AE, Stein, DR, Thiffault, I, Voinova, VY, Somers, MJG, Ferguson, MA, Traum, AZ, Daouk, GH, Daga, A, Rodig, NM, Terhal, PA, van Binsbergen, E, Eid, LA, Tasic, V, Rasouly, HMilo, Lim, TY, Ahram, DF, Gharavi, AG, Reutter, HM, Rehm, HL, MacArthur, DG, Lek, M, Laricchia, KM, Lifton, RP, Xu, H, Mane, SM, Sanna-Cherchi, S, Sharrocks, AD, Raught, B, Fisher, SE, Bouchard, M, Khokha, MK, Shril, S, Hildebrandt, F
JournalAm J Hum Genet
Date Published2020 10 01
KeywordsAmphibian Proteins, Animals, Case-Control Studies, Child, Child, Preschool, DNA-Binding Proteins, Epigenesis, Genetic, Family, Female, Forkhead Transcription Factors, Heterozygote, Humans, Infant, Larva, Male, Mice, Mice, Knockout, Morpholinos, Mutation, Pedigree, Protein Binding, Repressor Proteins, Transcription Factors, Urinary Tract, Urogenital Abnormalities, Whole Exome Sequencing, Xenopus

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.

Alternate JournalAm J Hum Genet
PubMed ID32891193
PubMed Central IDPMC7536580
Grant ListMC_UU_00007/3 / MR / Medical Research Council / United Kingdom
UM1 HG008900 / HG / NHGRI NIH HHS / United States
P20 DK116191 / DK / NIDDK NIH HHS / United States
R01 DK088767 / DK / NIDDK NIH HHS / United States
P50 HD103524 / HD / NICHD NIH HHS / United States
P30 DK079310 / DK / NIDDK NIH HHS / United States
R01 DK078226 / DK / NIDDK NIH HHS / United States
T32 GM007205 / GM / NIGMS NIH HHS / United States
R01 HD102186 / HD / NICHD NIH HHS / United States
R01 DK103184 / DK / NIDDK NIH HHS / United States
R01 DK115574 / DK / NIDDK NIH HHS / United States