Autosomal dominant polycystic kidney disease in absence of renal cyst formation illustrates genetic interaction between <i>WT1</i> and <i>PKD1</i>.

Abstract

Autosomal dominant polycystic kidney disease (ADPKD), caused by pathogenic variants of either <i>PKD1</i> or <i>PKD2</i>, is characterised by wide interfamilial and intrafamilial phenotypic variability. This study aimed to determine the molecular basis of marked clinical variability in ADPKD family members and sought to analyse whether alterations of <i>WT1</i> (Wilms tumour 1), encoding a regulator of gene expression, may have an impact on renal cyst formation. ADPKD family members underwent clinical and molecular evaluation. Functionally, <i>Pkd1</i> mRNA and protein expression upon <i>Wt1</i> knockdown was evaluated in mouse embryonic kidneys and mesonephric M15 cells. By renal gene panel analysis, we identified two pathogenic variants in an individual with maternal history of ADPKD, however, without cystic kidneys but polycystic liver disease: a known <i>PKD1</i> missense variant (c.8311G>A, p.Glu2771Lys) and a known de novo <i>WT1</i> splice site variant (c.1432+4C>T). The latter was previously associated with imbalanced +/-KTS isoform ratio of <i>WT1</i>. In ex vivo organ cultures from mouse embryonic kidneys, <i>Wt1</i> knockdown resulted in decreased <i>Pkd1</i> expression on mRNA and protein level. While the role of WT1 in glomerulopathies has been well established, this report by illustrating genetic interaction with <i>PKD1</i> proposes <i>WT1</i> as potential modifier in ADPKD.