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Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations

Dervla M Connaughton 1, 2 Rufeng Dai 1, 3 Danielle J Owen 4 Jonathan Marquez 5 Nina Mann 1 Adda L Graham-Paquin 6 Makiko Nakayama 1 Etienne Coyaud 7, 8, 9 Estelle M.N. Laurent 7, 8, 9 Jonathan R St-Germain 8, 9 Lot Snijders Blok 10, 11, 12 Arianna Vino 10 Verena Klämbt 1 Konstantin Deutsch 1 Chen-Han Wilfred Wu 1 Caroline M Kolvenbach 1 Franziska Kause 1 Isabel Ottlewski 1 Ronen Schneider 1 Thomas M Kitzler 1 Amar J Majmundar 1 Florian Buerger 1 Ana C Onuchic-Whitford 1, 13 Mao Youying 1 Amy Kolb 1 Daanya Salmanullah 1 Evan Chen 1 Amelie T van Der Ven 1 Jia Rao 3 Hadas Ityel 1 Steve Seltzsam 1 Johanna M Rieke 1 Jing Chen 1 Asaf Vivante 1, 14 Daw-Yang Hwang 1 Stefan Kohl 1 Gabriel C Dworschak 1 Tobias Hermle 1 Mariëlle Alders 15 Tobias Bartolomaeus 16 Stuart Bauer 1 Michelle Baum 1 Eva Brilstra 17 Thomas Challman 18 Jacob Zyskind 19 Carrie Costin 20 Katrina Dipple 21 Floor Duijkers 15 Marcia Ferguson 22 David Fitzpatrick 23 Roger Fick 24 Ian Glass 21 Peter Hulick 25 Antonie Kline 22 Ilona Krey 16 Selvin Kumar 26 Weining Lu 27 Elysa Marco 28 Ingrid Wentzensen 19 Heather Mefford 21 Konrad Platzer 16 Inna Povolotskaya 29, 30 Juliann Savatt 18 Natalia Shcherbakova 29, 30 Prabha Senguttuvan 31 Audrey Squire 32 Deborah Stein 1 Isabelle Thiffault 33, 34 Victoria Voinova 29, 30 Michael J.G. Somers 1 Michael Ferguson 1 Avram Traum 1 Ghaleb Daouk 1 Ankana Daga 1 Nancy Rodig 1 Paulien Terhal 17 Ellen van Binsbergen 17 Loai Eid 35 Velibor Tasic 36 Hila Milo Rasouly 37 Tze Lim 37 Dina Ahram 37 Ali Gharavi 37 Heiko Reutter 38 Heidi Rehm 39 Daniel Mc Arthur 39 Monkol Lek 39 Kristen Laricchia 39 Richard Lifton 40 Hong Xu 3 Shrikant Mane 41 Simone Sanna-Cherchi 37 Andrew Sharrocks 4 Brian Raught 8, 9 Simon Fisher 10 Maxime Bouchard 6 Mustafa Khokha 5 Shirlee Shril 1 Friedhelm Hildebrandt 1, 42, * 
* Corresponding author
Abstract : 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 CA-KUT, 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 morpho-lino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and cranio-facial 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 endoge-nous 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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Submitted on : Monday, October 12, 2020 - 1:29:12 PM
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Dervla M Connaughton, Rufeng Dai, Danielle J Owen, Jonathan Marquez, Nina Mann, et al.. Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations. American Journal of Human Genetics, Elsevier (Cell Press), 2020, 107 (4), pp.727-742. ⟨10.1016/j.ajhg.2020.08.013⟩. ⟨inserm-02964365⟩



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