UPK3A – Congenital Anomalies of the Kidney and Urinary Tract

Uroplakin IIIA, encoded by UPK3A, is an integral membrane protein of urothelial plaques and plays a key role in ureteric and bladder development. Disruption of its function has been hypothesized to contribute to congenital anomalies of the kidney and urinary tract (Congenital Anomalies of the Kidney and Urinary Tract).

A de novo heterozygous missense variant, c.605G>A (p.Gly202Asp), was reported in a patient with unilateral multicystic dysplastic kidneys and showed segregation consistent with disease in one family (PMID:16731295).

Targeted exome sequencing of 94 Korean CAKUT patients identified a pathogenic UPK3A variant among seven SNVs across five known genes, implicating UPK3A in approximately 1% of cases (PMID:32164334).

In a two-stage association study of 409 Dutch primary VUR patients versus 1,446 controls, common UPK3A SNPs showed a non-significant trend toward association with duplex collecting system and vesicoureteral reflux, but none reached statistical significance (PMID:22558067).

Functional studies demonstrate that UPIIIA knockout mice develop urothelial plaque anomalies and vesicoureteral reflux, mirroring human CAKUT phenotypes. The de novo p.Gly202Asp variant lies within a conserved extracellular domain, consistent with a loss-of-function mechanism (PMID:16731295).

Overall, the current data support a Limited association of UPK3A with CAKUT based on two rare heterozygous variants in humans and non-significant common variant trends, bolstered by Moderate functional concordance in murine models. Key take-home: UPK3A merits inclusion in diagnostic gene panels for CAKUT, although further genetic and mechanistic studies are required to clarify its clinical impact.

References

• PloS one • 2012 • Genes in the ureteric budding pathway: association study on vesico-ureteral reflux patients. PMID:22558067
• Journal of Clinical Medicine • 2020 • Targeted Exome Sequencing Provided Comprehensive Genetic Diagnosis of Congenital Anomalies of the Kidney and Urinary Tract. PMID:32164334
• American journal of kidney diseases • 2006 • Mutations in Uroplakin IIIA are a rare cause of renal hypodysplasia in humans. PMID:16731295

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