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)
1
Boston Children's Hospital
2 UWO - University of Western Ontario
3 Fudan University [Shanghai]
4 University of Manchester [Manchester]
5 Yale University [New Haven]
6 McGill University = Université McGill [Montréal, Canada]
7 PRISM - Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192
8 University Health Network [Toronto, ON, Canada]
9 University of Toronto
10 Max Planck Institute for Psycholinguistics
11 Donders Institute for Brain, Cognition and Behaviour
12 Radboud University Medical Center [Nijmegen]
13 BWH - Brigham & Women’s Hospital [Boston]
14 TAU - Tel Aviv University
15 UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam
16 Leipzig University / Universität Leipzig
17 University Medical Center [Utrecht]
18 ADMI - Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA]
19 GeneDx [Gaithersburg, MD, USA]
20 University of Akron
21 University of Washington [Seattle]
22 William Harvey Research Institute, Barts and the London Medical School
23 Edin. - University of Edinburgh
24 Mary Bridge Childrens Hospital [Tacoma, WA, USA]
25 NorthShore University HealthSystem [Evanston, IL, USA]
26 Hospital for Children - Institute of Child Health [Tamil Nadu, India]
27 BU - Boston University [Boston]
28 Cortica Healthcare [San Rafael, CA, USA]
29 Moscow Medical Institute of Health Ministry [Moscow, Russia]
30 Pirogov Russian National Research Medical University
31 Dr. Mehta's Hospitals [Tamil Nadu, India]
32 Seattle Children’s Hospital
33 Children's Mercy Hospital [Kansas City]
34 UMKC - University of Missouri [Kansas City]
35 Neuro Spinal Hospital [Dubai, UAE]
36 University Children’s Hospital [Skopje, Macédoine]
37 Columbia University [New York]
38 University Hospital Bonn
39 Massachusetts General Hospital [Boston]
40 Rockefeller University [New York]
41 YSM - Yale School of Medicine [New Haven, Connecticut]
42 HMS - Harvard Medical School [Boston]
2 UWO - University of Western Ontario
3 Fudan University [Shanghai]
4 University of Manchester [Manchester]
5 Yale University [New Haven]
6 McGill University = Université McGill [Montréal, Canada]
7 PRISM - Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192
8 University Health Network [Toronto, ON, Canada]
9 University of Toronto
10 Max Planck Institute for Psycholinguistics
11 Donders Institute for Brain, Cognition and Behaviour
12 Radboud University Medical Center [Nijmegen]
13 BWH - Brigham & Women’s Hospital [Boston]
14 TAU - Tel Aviv University
15 UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam
16 Leipzig University / Universität Leipzig
17 University Medical Center [Utrecht]
18 ADMI - Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA]
19 GeneDx [Gaithersburg, MD, USA]
20 University of Akron
21 University of Washington [Seattle]
22 William Harvey Research Institute, Barts and the London Medical School
23 Edin. - University of Edinburgh
24 Mary Bridge Childrens Hospital [Tacoma, WA, USA]
25 NorthShore University HealthSystem [Evanston, IL, USA]
26 Hospital for Children - Institute of Child Health [Tamil Nadu, India]
27 BU - Boston University [Boston]
28 Cortica Healthcare [San Rafael, CA, USA]
29 Moscow Medical Institute of Health Ministry [Moscow, Russia]
30 Pirogov Russian National Research Medical University
31 Dr. Mehta's Hospitals [Tamil Nadu, India]
32 Seattle Children’s Hospital
33 Children's Mercy Hospital [Kansas City]
34 UMKC - University of Missouri [Kansas City]
35 Neuro Spinal Hospital [Dubai, UAE]
36 University Children’s Hospital [Skopje, Macédoine]
37 Columbia University [New York]
38 University Hospital Bonn
39 Massachusetts General Hospital [Boston]
40 Rockefeller University [New York]
41 YSM - Yale School of Medicine [New Haven, Connecticut]
42 HMS - Harvard Medical School [Boston]
Etienne Coyaud
- Fonction : Auteur
- PersonId : 1180207
- IdHAL : etienne-coyaud
- ORCID : 0000-0002-5893-4557
David Fitzpatrick
- Fonction : Auteur
- PersonId : 764605
- ORCID : 0000-0003-4861-969X
Peter Hulick
- Fonction : Auteur
- PersonId : 791345
- ORCID : 0000-0001-8397-4078
Isabelle Thiffault
- Fonction : Auteur
- PersonId : 791599
- ORCID : 0000-0001-7987-6731
Shrikant Mane
- Fonction : Auteur
- PersonId : 795719
- ORCID : 0000-0002-3267-5139
Brian Raught
- Fonction : Auteur
Friedhelm Hildebrandt
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 1079150
Connectez-vous pour contacter l'auteur
Résumé
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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