Abstract: SA-PO0619
REN p.L16del Mutation Is Associated with a Milder In Vitro and Clinical Phenotype Compared with Other Signal Peptide Mutations
Session Information
- Monogenic Kidney Diseases: Tubular and Other
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Zivna, Martina, Univerzita Karlova, Prague, Czechia
- Kidd, Kendrah O., Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
- Claes, Kathleen, UZ Leuven, Leuven, Flanders, Belgium
- Ong, Albert C., The University of Sheffield, Sheffield, England, United Kingdom
- Corey, Howard E., Atlantic Health System Inc, Morristown, New Jersey, United States
- Cross, Sarita K., Mountain Kidney and Hypertension Associates, Asheville, North Carolina, United States
- Zaritsky, Joshua, Phoenix Children's Hospital, Phoenix, Arizona, United States
- Kopel, Tal H., Universite de Montreal, Montreal, Quebec, Canada
- Vamenta-Morris, Helga B., Columbia Nephrology, Columbia, South Carolina, United States
- Rumancik, Mark, Nephrology Associates of Northern Illinois and Indiana, Oak Brook, Illinois, United States
- Moe, Sharon M., Indiana University School of Medicine, Indianapolis, Indiana, United States
- Kmoch, Stanislav, Univerzita Karlova, Prague, Czechia
- Bleyer, Anthony J., Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
Background
Autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN) presents with hyporeninemic hypoaldosteronism, hyperkalemia, mild hypotension, acidemia and hyperuricemia leading to slowly progressive chronic kidney disease. ADTKD-REN causing mutations have been identified in all three functional renin domains: signal peptide (SP), prorenin, and mature renin. SP mutations are associated with earlier clinical presentation and faster progression than mutations in other domains. Here we report on the most prevalent p.L16del mutation in the SP and compare its phenotype with other SP mutations.
Methods
We reviewed the Wake Forest Registry for individuals with the REN p.L16del mutation and their outcomes. To assess the effect on prorenin and renin synthesis and secretion, we transiently expressed wild type, p.L13Q, p.L16del, p.L16P, p.W17R and p.C20R SP mutationsin in HEK293 cells and characterized their properties.
Results
Nine of 22 (41%) ADTKD-REN families in the Wake Forest REN registry have the p.L16del mutation. Clinical information was available for 33 individuals with p.L16del and 20 individuals with missense SP mutations. Age of presentation for p.L16del was 18.8±9.4 years vs 12.0±8.2 years for missense SP mutations (P=0.02). Individuals with p.L16del were more likely to present with gout (48% vs 0%, P=0.001) and less likely to present with CKD (9.5% vs 50%, p<0.01). Males with p.L16del were more likely to present with gout (78% vs 25%, P=0.02) and females with anemia (22% vs 75%,P=0.02). The average age of kidney failure for p.L16del was 54.2±11.5 (n=14) vs 51.4±11.0 for other SP mutations (n=11, P=0.538). In vitro studies showed the p.L16del was the only SP mutation that allows for at least partial (50% of the wild type) co-translational translocation, preprorenin processing and prorenin and renin secretion.
Conclusion
The p.L16del variant is the most prevalent mutation causing ADTKD-REN. It is associated with milder cellular effects and correspondingly has a milder clinical presentation, though power was limited to detect differences in ESRD age. This information will help inform patients with this condition and their physicians.
Funding
- Private Foundation Support