2. Academic Validation
  3. Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations

Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations

  • Am J Hum Genet. 2020 Oct 1;107(4):727-742. doi: 10.1016/j.ajhg.2020.08.013.
Dervla M Connaughton 1,  Rufeng Dai 2,  Danielle J Owen 3,  Jonathan Marquez 4,  Nina Mann 5,  Adda L Graham-Paquin 6,  Makiko Nakayama 5,  Etienne Coyaud 7,  Estelle M N Laurent 7,  Jonathan R St-Germain 8,  Lot Snijders Blok 9,  Arianna Vino 10,  Verena Klämbt 5,  Konstantin Deutsch 5,  Chen-Han Wilfred Wu 5,  Caroline M Kolvenbach 5,  Franziska Kause 5,  Isabel Ottlewski 5,  Ronen Schneider 5,  Thomas M Kitzler 5,  Amar J Majmundar 5,  Florian Buerger 5,  Ana C Onuchic-Whitford 11,  Mao Youying 5,  Amy Kolb 5,  Daanya Salmanullah 5,  Evan Chen 5,  Amelie T van der Ven 5,  Jia Rao 12,  Hadas Ityel 5,  Steve Seltzsam 5,  Johanna M Rieke 5,  Jing Chen 5,  Asaf Vivante 13,  Daw-Yang Hwang 5,  Stefan Kohl 5,  Gabriel C Dworschak 5,  Tobias Hermle 5,  Mariëlle Alders 14,  Tobias Bartolomaeus 15,  Stuart B Bauer 16,  Michelle A Baum 5,  Eva H Brilstra 17,  Thomas D Challman 18,  Jacob Zyskind 19,  Carrie E Costin 20,  Katrina M Dipple 21,  Floor A Duijkers 22,  Marcia Ferguson 23,  David R Fitzpatrick 24,  Roger Fick 25,  Ian A Glass 21,  Peter J Hulick 26,  Antonie D Kline 23,  Ilona Krey 27,  Selvin Kumar 28,  Weining Lu 29,  Elysa J Marco 30,  Ingrid M Wentzensen 19,  Heather C Mefford 21,  Konrad Platzer 15,  Inna S Povolotskaya 31,  Juliann M Savatt 18,  Natalia V Shcherbakova 31,  Prabha Senguttuvan 32,  Audrey E Squire 33,  Deborah R Stein 5,  Isabelle Thiffault 34,  Victoria Y Voinova 31,  Michael J G Somers 5,  Michael A Ferguson 5,  Avram Z Traum 5,  Ghaleb H Daouk 5,  Ankana Daga 5,  Nancy M Rodig 5,  Paulien A Terhal 17,  Ellen van Binsbergen 17,  Loai A Eid 35,  Velibor Tasic 36,  Hila Milo Rasouly 37,  Tze Y Lim 37,  Dina F Ahram 37,  Ali G Gharavi 37,  Heiko M Reutter 38,  Heidi L Rehm 39,  Daniel G MacArthur 39,  Monkol Lek 39,  Kristen M Laricchia 39,  Richard P Lifton 40,  Hong Xu 12,  Shrikant M Mane 41,  Simone Sanna-Cherchi 37,  Andrew D Sharrocks 3,  Brian Raught 8,  Simon E Fisher 42,  Maxime Bouchard 6,  Mustafa K Khokha 4,  Shirlee Shril 5,  Friedhelm Hildebrandt 43
Affiliations

Affiliations

  • 1 Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Nephrology, Department of Medicine, University Hospital - London Health Sciences Centre, Schulich School of Medicine & Dentistry, Western University, 339 Windermere Road, London, ON N6A 5A5, Canada.
  • 2 Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Nephrology, Children's Hospital of Fudan University, 201102 Shanghai, China.
  • 3 Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK.
  • 4 Pediatric Genomics Discovery Program, Department of Pediatrics and Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
  • 5 Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 6 Rosalind & Morris Goodman Cancer Research Centre and Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada.
  • 7 Princess Margaret Cancer Centre, University Health Network & Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Univ. Lille, Inserm, CHU Lille, U1192 - Protéomique Réponse Inflammatoire Spectrométrie de Masse - PRISM, 59000 Lille, France.
  • 8 Princess Margaret Cancer Centre, University Health Network & Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • 9 Language and Genetics Department, Max Planck Institute for Psycholinguistics, 6525 XD Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6500HE Nijmegen, the Netherlands; Human Genetics Department, Radboud University Medical Center, 6500HB Nijmegen, the Netherlands.
  • 10 Language and Genetics Department, Max Planck Institute for Psycholinguistics, 6525 XD Nijmegen, the Netherlands.
  • 11 Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 12 Department of Nephrology, Children's Hospital of Fudan University, 201102 Shanghai, China.
  • 13 Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Tel Aviv University, Faculty of Medicine, Tel Aviv-Yafo 6997801, Israel.
  • 14 Amsterdam UMC, University of Amsterdam, Department of Clinical Genetics, Meibergdreef 9, 1105 Amsterdam, Netherlands.
  • 15 Institute of Human Genetics, University of Leipzig Medical Center, Philipp-Rosenthal- Straße 55, 04103 Leipzig, Germany.
  • 16 Department of Urology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 17 Department of Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.
  • 18 Geisinger, Autism & Developmental Medicine Institute, 100 N Academy Avenue, Danville, PA 17822, USA.
  • 19 Department of Clinical Genomics, GeneDx, 207 Perry Pkwy, Gaithersburg, MD 20877, USA.
  • 20 Department of Clinical Genetics, Akron Children's Hospital, One Perkins Square, Akron, OH 44308, USA.
  • 21 Division of Genetic Medicine, Department of Pediatrics, University of Washington, 4800 Sand Point Way NE, Seattle, WA 98105, USA.
  • 22 Department of Clinical Genetics, University of Amsterdam, 1012 WX Amsterdam, the Netherlands.
  • 23 Department of Clinical Genetics, Harvey Institute for Human Genetics, 6701 Charles St, Towson, MD 21204, USA.
  • 24 MRC Institute of Genetics & Molecular Medicine, Royal Hospital for Sick Children, The University of Edinburgh, 2XU, Crewe Rd S, Edinburgh EH4 2XU, UK.
  • 25 Mary Bridge Childrens Hospital, 316 Martin Luther King JR Way, Tacoma, WA 98405, USA.
  • 26 Center for Medical Genetics, NorthShore University HealthSystem, 1000 Central Street, Suite 610, Evanston, IL 60201, USA.
  • 27 Institute of Human Genetics, University of Leipzig Medical Center, Philipp-Rosenthal- Straße 55, 04103 Leipzig, Germany; Swiss Epilepsy Center, Klinik Lengg, Bleulerstrasse 60, 8000 Zürich, Switzerland.
  • 28 Department of Pediatric Nephrology, Institute of Child Health and Hospital for Children, Tamil Salai, Egmore, Chennai, Tamil Nadu 600008, India.
  • 29 Renal Section, Department of Medicine, Boston University Medical Center, 650 Albany Street, Boston, MA 02118, USA.
  • 30 Cortica Healthcare, 4000 Civic Center Drive, Ste 100, San Rafael, CA 94939, USA.
  • 31 Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University of the Russian Ministry of Health, Moscow 117997, Russia.
  • 32 Department of Pediatric Nephrology, Dr. Mehta's Multi-Specialty Hospital, No.2, Mc Nichols Rd, Chetpet, Chennai, Tamil Nadu 600031, India.
  • 33 Seattle Children's Hospital, Department of Genetic Medicine, 4800 Sand Point Way NE, Seattle, WA 98105, USA.
  • 34 Center for Pediatric Genomic Medicine, Children's Mercy Hospital, 2401 Gillham Rd, Kansas City, MO 64108, USA; Department of Pathology and Laboratory Medicine, Children's Mercy Hospitals, Kansas City, MO 64108, USA; University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, 5000 Holmes St, Kansas City, MO 64110, USA.
  • 35 Pediatric Nephrology Department, Dubai Hospital, Dubai, United Arab Emirates.
  • 36 Medical Faculty Skopje, University Children's Hospital, Skopje 1000, North Macedonia.
  • 37 Division of Nephrology, Columbia University, 630 W 168th St, New York, NY 10032, USA.
  • 38 Institute of Human Genetics, University Hospital Bonn, 53127 Bonn, Germany; Section of Neonatology and Pediatric Intensive Care, Clinic for Pediatrics, University Hospital Bonn, Adenauerallee 119, 53313 Bonn, Germany.
  • 39 Analytic and Translational Genetics Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
  • 40 The Rockefeller University, 1230 York Ave, New York, NY 10065, USA.
  • 41 Department of Genetics, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06510, USA.
  • 42 Language and Genetics Department, Max Planck Institute for Psycholinguistics, 6525 XD Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6500HE Nijmegen, the Netherlands.
  • 43 Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 32891193 DOI: 10.1016/j.ajhg.2020.08.013
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 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.

Keywords

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

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