PKD1 5’UTR variants are a rare cause of disease in ADPKD and suggest a new focus for therapeutic development
Wedd, Laura, Hort, Yvonne, Patel, Chirag, Sayer, John A., Rius, Rocio, Mallett, Andrew J., Cottle, Denny L., Smyth, Ian M., Furlong, Timothy, Shine, John, and Mallawaarachchi, Amali (2025) PKD1 5’UTR variants are a rare cause of disease in ADPKD and suggest a new focus for therapeutic development. European Journal of Human Genetics, 34. pp. 61-69.
|
PDF (Published Version)
- Published Version
Available under License Creative Commons Attribution. Download (930kB) | Preview |
Abstract
Autosomal Dominant Polycystic Kidney Disease (ADPKD), caused by pathogenic variants in PKD1 and PKD2, is the most common monogenic cause of kidney failure. Approximately 10% of ADPKD patients remain undiagnosed after coding-region focused genomic testing. Non-coding variants in regulatory regions are not an established cause of disease in ADPKD. We performed regulatory region analysis in a primary cohort of undiagnosed ADPKD patients (n = 20) and then extended this analysis to patients with undiagnosed cystic kidney disease within the Australian KidGen cohort (n = 42) and the Genomics England rare disease cohort (n = 1320). Through this genomic analysis we identified two rare, potentially disease-causing variants in the PKD1 5′untranslated region (UTR). We then designed a PKD1 5′UTR-luciferase translation assay to characterise these variants in vitro, which showed that a PKD1 variant c.−69dupG, reduced the translation efficiency of the main PKD1 open reading frame by ~87% compared to wildtype (p < 0.0001). The human PKD1 5′UTR contains two upstream open reading frames (uORFs). Using our model, we knocked-out the upstream open reading frames of the wildtype PKD1 5′UTR sequence, which increased expression of wildtype polycystin-1 (130%, p < 0.0001). We show that PKD1 5′-UTR variants are a currently overlooked rare cause of disease in ADPKD and that analysis of this region should be included in variant analysis pathways to increase diagnostic rates. In addition, we show that manipulation of the wildtype 5′UTR sequence can increase polycystin-1 expression, providing insights into regulation of PKD1 and suggested new approaches for therapeutic intervention in this haplo-insufficient disease.
| Item ID: | 89268 |
|---|---|
| Item Type: | Article (Research - C1) |
| ISSN: | 1476-5438 |
| Copyright Information: | © The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
| Date Deposited: | 20 Jul 2026 07:34 |
| FoR Codes: | 32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320214 Nephrology and urology @ 100% |
| SEO Codes: | 20 HEALTH > 2001 Clinical health > 200105 Treatment of human diseases and conditions @ 100% |
| More Statistics |
Actions (Repository Staff Only)
 |
Item Control Page |