1. Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations
- Author
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Danielle J. Owen, David FitzPatrick, Nina Mann, Stuart B. Bauer, Ilona Krey, Heather C Mefford, Jacob Zyskind, Roger Fick, Ana C. Onuchic-Whitford, Floor A. M. Duijkers, Etienne Coyaud, Simon E. Fisher, Juliann M. Savatt, Richard P. Lifton, Isabel Ottlewski, Amelie T. van der Ven, Peter J. Hulick, Nancy Rodig, Michelle A. Baum, Marielle Alders, Elysa J. Marco, Konrad Platzer, Ghaleb Daouk, Hadas Ityel, Eva H. Brilstra, Ian A. Glass, Heiko Reutter, Adda L. Graham-Paquin, Makiko Nakayama, Michael A. J. Ferguson, Amy Kolb, Weining Lu, Florian Buerger, Prabha Senguttuvan, Marcia Ferguson, Ronen Schneider, Isabelle Thiffault, Hila Milo Rasouly, Verena Klämbt, Tobias Bartolomaeus, Evan Chen, Mao Youying, Amar J. Majmundar, Jia Rao, Carrie Costin, Dina Ahram, Ali G. Gharavi, Lot Snijders Blok, Avram Z. Traum, Franziska Kause, Konstantin Deutsch, Arianna Vino, Dervla M. Connaughton, Antonie D. Kline, Deborah R. Stein, Daanya Salmanullah, Maxime Bouchard, Estelle M.N. Laurent, Audrey Squire, Daniel G. MacArthur, Kristen M. Laricchia, Asaf Vivante, Thomas M. Kitzler, Jonathan St-Germain, Brian Raught, Heidi L. Rehm, Ellen van Binsbergen, Chen Han Wilfred Wu, Caroline M. Kolvenbach, Monkol Lek, Selvin Kumar, Jing Chen, Mustafa K. Khokha, Ankana Daga, Hong Xu, Andrew D. Sharrocks, N. V. Shcherbakova, Simone Sanna-Cherchi, Inna S. Povolotskaya, Tze Y Lim, Johanna M. Rieke, Katrina M. Dipple, Gabriel C. Dworschak, Michael J. Somers, Tobias Hermle, Stefan Kohl, Steve Seltzsam, Victoria Y. Voinova, Shirlee Shril, Ingrid M. Wentzensen, Daw Yang Hwang, Velibor Tasic, Shrikant Mane, Jonathan Marquez, Friedhelm Hildebrandt, Rufeng Dai, Paulien A Terhal, Loai A. Eid, Thomas D. Challman, Boston Children's Hospital, Harvard Medical School [Boston] (HMS), University of Western Ontario (UWO), Fudan University [Shanghai], University of Manchester [Manchester], Yale University [New Haven], McGill University = Université McGill [Montréal, Canada], Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University Health Network, University of Toronto, Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft, Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], Radboud University Medical Center [Nijmegen], Brigham & Women’s Hospital [Boston] (BWH), Tel Aviv University (TAU), University of Amsterdam [Amsterdam] (UvA), Universität Leipzig, University Medical Center [Utrecht], Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), GeneDx [Gaithersburg, MD, USA], University of Akron, University of Washington [Seattle], William Harvey Research Institute, Barts and the London Medical School, University of Edinburgh, Mary Bridge Childrens Hospital [Tacoma, WA, USA], NorthShore University HealthSystem [Evanston, IL, USA], Institute of Child Health [Tamil Nadu, India] (Hospital for Children), Boston University [Boston] (BU), Cortica Healthcare [San Rafael, CA, USA], Moscow Medical Institute of Health Ministry [Moscow, Russia], Pirogov Russian National Research Medical University, Dr. Mehta's Hospitals [Tamil Nadu, India], Seattle Children’s Hospital, Children's Mercy Hospital [Kansas City], University of Missouri [Kansas City] (UMKC), University of Missouri System, Neuro Spinal Hospital [Dubai, UAE], University Children’s Hospital [Skopje, Macédoine], Columbia University [New York], University Hospital Bonn, Massachusetts General Hospital [Boston], Rockefeller University [New York], Yale School of Medicine [New Haven, Connecticut] (YSM), Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Radboud university [Nijmegen], Tel Aviv University [Tel Aviv], Universität Leipzig [Leipzig], Pirogov Russian National Research Medical University [Moscow, Russia], Yale University School of Medicine, INSERM, Université de Lille, Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192, and SALZET, Michel
- Subjects
0301 basic medicine ,Male ,Morpholino ,Xenopus ,030232 urology & nephrology ,Endogenous retrovirus ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,transcription regulator ,Interactome ,Epigenesis, Genetic ,Morpholinos ,Pathogenesis ,ZNF198 ,Mice ,0302 clinical medicine ,whole-exome sequencing ,Child ,Urinary Tract ,Genetics (clinical) ,Exome sequencing ,Genetics ,Mice, Knockout ,ZMYM2 ,genetic kidney disease ,Forkhead Transcription Factors ,FOXP1 ,3. Good health ,Pedigree ,extra-renal features ,DNA-Binding Proteins ,Child, Preschool ,Larva ,syndromic CAKUT ,Female ,Protein Binding ,Neuroinformatics ,Heterozygote ,Biology ,Article ,Amphibian Proteins ,03 medical and health sciences ,Exome Sequencing ,[SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,Gene silencing ,Animals ,Humans ,Family ,Transcription factor ,FIM ,Infant ,Repressor Proteins ,030104 developmental biology ,genomic analysis ,Case-Control Studies ,Urogenital Abnormalities ,congenital anomalies of the kidney and urinary tract ,Mutation ,Transcription Factors - Abstract
International audience; 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.
- Published
- 2020