TSHZ3 – Congenital Anomaly of Kidney and Urinary Tract

TSHZ3 encodes the teashirt zinc finger homeobox 3 transcription factor, critically involved in mesenchymal differentiation of the urinary tract and neuronal development. Monoallelic deletions at 19q12–q13.11 encompassing TSHZ3 have long been linked to intellectual disability, behavioral issues, and CAKUT in humans and mice, suggesting haploinsufficiency as a disease mechanism TSHZ3–Congenital anomaly of kidney and urinary tract.

In a single‐patient report, a heterozygous frameshift variant c.119_120dup (p.Pro41SerfsTer79) was identified by exome sequencing in a 7-year-old girl with intellectual disability, behavioral issues, pyelocaliceal dilatation, and urethral stenosis, recapitulating the CAKUT phenotype seen in TSHZ3 deletion carriers (1 proband) (PMID:36553458).

In a cohort of 301 families with CAKUT, five distinct rare heterozygous missense variants including c.172A>G (p.Ser58Gly) were found in 12 patients from 9 families (3% of families) with multicystic dysplastic kidney (MCDK), hydronephrosis, hydroureter, ureteropelvic junction obstruction, and genital anomalies, overlapping murine Tshz3‐mutant phenotypes (PMID:39420202).

Overall variant spectrum comprises 1 predicted loss-of-function frameshift and 5 missense changes in the N-terminal region. TSHZ3 variants in CAKUT cases were significantly enriched versus gnomAD controls (p<0.001) and included familial segregation in two affected siblings (1 additional relative) (PMID:39420202).

Functional studies demonstrate TSHZ3 expression in human fetal kidney and murine ureter/kidney mesenchyme at E11.5–14.5; mutant proteins show disrupted SOX9 and myocardin binding, and nephrectomy specimens exhibit disorganized smooth muscle layers in the renal pelvis, concordant with Tshz3−/− mouse models (PMID:39420202).

No contradictory reports have emerged. Taken together, heterozygous variants in TSHZ3 cause CAKUT via haploinsufficiency, with strong genetic and experimental evidence. Inclusion of TSHZ3 in diagnostic CAKUT gene panels is recommended for early detection and management.

References

• Genes • 2022 • A TSHZ3 Frame-Shift Variant Causes Neurodevelopmental and Renal Disorder Consistent with Previously Described Proximal Chromosome 19q13.11 Deletion Syndrome. PMID:36553458
• European journal of human genetics : EJHG • 2025 • Heterozygous variants in the teashirt zinc finger homeobox 3 (TSHZ3) gene in human congenital anomalies of the kidney and urinary tract. PMID:39420202

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