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. Epub 2020 Sep 4.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amphibian Proteins / antagonists & inhibitors
  • Amphibian Proteins / genetics
  • Amphibian Proteins / metabolism
  • Animals
  • Case-Control Studies
  • Child
  • Child, Preschool
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Epigenesis, Genetic*
  • Family
  • Female
  • Forkhead Transcription Factors / genetics*
  • Forkhead Transcription Factors / metabolism
  • Heterozygote
  • Humans
  • Infant
  • Larva / genetics
  • Larva / growth & development
  • Larva / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Morpholinos / genetics
  • Morpholinos / metabolism
  • Mutation*
  • Pedigree
  • Protein Binding
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Urinary Tract / abnormalities
  • Urinary Tract / metabolism*
  • Urogenital Abnormalities / genetics*
  • Urogenital Abnormalities / metabolism
  • Urogenital Abnormalities / pathology
  • Whole Exome Sequencing
  • Xenopus


  • Amphibian Proteins
  • DNA-Binding Proteins
  • FOXP1 protein, human
  • Forkhead Transcription Factors
  • Morpholinos
  • Repressor Proteins
  • Transcription Factors
  • ZMYM2 protein, human