Back to Search
Start Over
Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.
- Source :
-
American journal of human genetics [Am J Hum Genet] 2020 Oct 01; Vol. 107 (4), pp. 727-742. Date of Electronic Publication: 2020 Sep 04. - Publication Year :
- 2020
-
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.<br /> (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Amphibian Proteins antagonists & inhibitors
Amphibian Proteins genetics
Amphibian Proteins metabolism
Animals
Case-Control Studies
Child
Child, Preschool
DNA-Binding Proteins metabolism
Family
Female
Forkhead Transcription Factors metabolism
Heterozygote
Humans
Infant
Larva genetics
Larva growth & development
Larva metabolism
Male
Mice
Mice, Knockout
Morpholinos genetics
Morpholinos metabolism
Pedigree
Protein Binding
Repressor Proteins metabolism
Transcription Factors metabolism
Urinary Tract abnormalities
Urogenital Abnormalities metabolism
Urogenital Abnormalities pathology
Exome Sequencing
Xenopus
DNA-Binding Proteins genetics
Epigenesis, Genetic
Forkhead Transcription Factors genetics
Mutation
Repressor Proteins genetics
Transcription Factors genetics
Urinary Tract metabolism
Urogenital Abnormalities genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6605
- Volume :
- 107
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- American journal of human genetics
- Publication Type :
- Academic Journal
- Accession number :
- 32891193
- Full Text :
- https://doi.org/10.1016/j.ajhg.2020.08.013