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Text
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<a href="http://doi.org/10.1016/j.ajhg.2020.08.013" target="_blank" rel="noreferrer noopener">http://doi.org/10.1016/j.ajhg.2020.08.013</a>
Pages
727-742
Issue
4
Volume
107
ISSN
1537-6605 0002-9297 0002-9297
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Update Year & Number
Hospital List
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Title
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Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.
Publisher
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American Journal of Human Genetics
Date
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2020
2020-10-01
Subject
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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
Creator
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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
Description
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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.
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<a href="http://doi.org/10.1016/j.ajhg.2020.08.013" target="_blank" rel="noreferrer noopener">10.1016/j.ajhg.2020.08.013</a>
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journalArticle
2020
Ahram DF
Alders M
American Journal of Human Genetics
Bartolomaeus T
Bauer SB
Baum MA
Blok LS
Bouchard M
Brilstra EH
Buerger F
Challman TD
Chen E
Chen J
congenital anomalies of the kidney and urinary tract
Connaughton DM
Costin CE
Coyaud E
Daga A
Dai R
Daouk GH
Deutsch K
Dipple KM
Duijkers FA
Dworschak GC
Eid LA
extra-renal features
Ferguson M
Ferguson MA
Fick R
FIM
Fisher SE
Fitzpatrick DR
genetic kidney disease
genomic analysis
Gharavi AG
Glass IA
Graham-Paquin AL
Hermle T
Hildebrandt F
Hospital List
Hulick PJ
Hwang D-Y
Ityel H
journalArticle
Kause F
Khokha MK
Kitzler TM
Klämbt V
Kline AD
Kohl S
Kolb A
Kolvenbach CM
Krey I
Kumar S
Laricchia KM
Laurent EMN
Lek M
Lifton RP
Lim TY
Lu W
MacArthur DG
Majmundar AJ
Mane SM
Mann N
Marco EJ
Marquez J
Mefford HC
Nakayama M
Onuchic-Whitford AC
Ottlewski I
Owen DJ
Platzer K
Povolotskaya IS
Rao Jia
Rasouly HM
Raught B
Rehm HL
Reutter HM
Rieke JM
Rodig NM
Salmanullah D
Sanna-Cherchi S
Savatt JM
Schneider R
Seltzsam S
Senguttuvan P
Sharrocks AD
Shcherbakova NV
Shril S
Somers MJG
Squire AE
St-Germain JR
Stein DR
syndromic CAKUT
Tasic V
Terhal PA
Thiffault I
transcription regulator
Traum AZ
van Binsbergen E
van der Ven AT
Vino A
Vivante A
Voinova VY
Wentzensen IM
whole-exome sequencing
Wu CW
Xu H
Youying M
ZMYM2
ZNF198
Zyskind J