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

Title

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

Creator

Connaughton DM; Dai R; Owen DJ; Marquez J; Mann N; Graham-Paquin AL; Nakayama M; Coyaud E; Laurent EMN; St-Germain JR; Blok LS; Vino A; Klämbt V; Deutsch K; Wu CW; 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 Jia; 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 HM; 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

Publisher

American Journal of Human Genetics

Date

2020
2020-10-01

Description

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.

Subject

congenital anomalies of the kidney and urinary tract; extra-renal features; FIM; genetic kidney disease; genomic analysis; syndromic CAKUT; transcription regulator; whole-exome sequencing; ZMYM2; ZNF198

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Format

journalArticle

Search for Full-text

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Pages

727-742

Issue

4

Volume

107

ISSN

1537-6605 0002-9297 0002-9297

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Hospital List

Citation

Connaughton DM; Dai R; Owen DJ; Marquez J; Mann N; Graham-Paquin AL; Nakayama M; Coyaud E; Laurent EMN; St-Germain JR; Blok LS; Vino A; Klämbt V; Deutsch K; Wu CW; 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 Jia; 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 HM; 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, “Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.,” NEOMED Bibliography Database, accessed June 21, 2021, https://neomed.omeka.net/items/show/11429.

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