Purpose Autosomal dominant polycystic kidney disease (ADPKD), caused by pathogenic variants of either PKD1 or PKD2, 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 WT1 (Wilms tumour 1), encoding a regulator of gene expression, may have an impact on renal cyst formation.
Methods ADPKD family members underwent clinical and molecular evaluation. Functionally, Pkd1 mRNA and protein expression upon Wt1 knockdown was evaluated in mouse embryonic kidneys and mesonephric M15 cells.
Results 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 PKD1 missense variant (c.8311G>A, p.Glu2771Lys) and a known de novo WT1 splice site variant (c.1432+4C>T). The latter was previously associated with imbalanced +/−KTS isoform ratio of WT1. In ex vivo organ cultures from mouse embryonic kidneys, Wt1 knockdown resulted in decreased Pkd1 expression on mRNA and protein level.
Conclusion While the role of WT1 in glomerulopathies has been well established, this report by illustrating genetic interaction with PKD1 proposes WT1 as potential modifier in ADPKD.
- renal medicine
- clinical genetics
- liver disease
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JM and KMK contributed equally.
Correction notice The article has been corrected since it was published Online First. The name of author Diana Le Duc has been corrected.
Contributors JM and JH wrote the manuscript and gathered clinical data from the index patient and her family, together with HS and RS. DLD performed and interpreted genetic analysis. KMK and HS conducted expression assays upon cell models. WJ and RS performed Western blot analysis. CK took care of WT1 expression analysis in primary patient cells.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.