ZMYM2 – Congenital Anomaly of Kidney and Urinary Tract

Heterozygous loss-of-function variants in the transcriptional corepressor ZMYM2 have been implicated in congenital anomaly of kidney and urinary tract (CAKUT). Whole-exome sequencing of 551 CAKUT probands identified 14 distinct heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families, all occurring de novo, supporting a dominant mechanism of disease (PMID:32891193).

The variant spectrum includes nonsense, frameshift and canonical splice-site changes, exemplified by c.1192C>T (p.Gln398Ter) (PMID:32891193). Segregation analysis revealed no additional familial transmission beyond de novo events, consistent with haploinsufficiency.

Functional studies in Xenopus tropicalis morpholino knockdowns showed failure of truncated ZMYM2 to rescue renal and craniofacial defects, and heterozygous Zmym2-deficient mice recapitulated CAKUT features with high penetrance (PMID:32891193). Proteomic assays demonstrated ZMYM2 interaction with epigenetic silencing complexes and binding to FOXP1, a transcription factor also linked to CAKUT, underscoring disruption of a corepressor network (PMID:32891193; PMID:34935912).

Collectively, these data define haploinsufficiency of ZMYM2 as a strong genetic cause of CAKUT, bridging human de novo mutation findings with concordant animal and cellular models. Genetic testing for ZMYM2 truncating alleles can inform diagnosis and counseling in CAKUT patients.

References

• American journal of human genetics • 2020 • Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations. PMID:32891193
• The Biochemical journal • 2022 • Proteomic analysis identifies ZMYM2 as endogenous binding partner of TBX18 protein in 293 and A549 cells. PMID:34935912

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