Abstract: SA-PO1012
A Novel Mutation in Podocyte-Specific Protease HtrA1 Is Associated with Glomerular Disease Progression
Session Information
- Glomerular Diseases: Podocyte Biology - II
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1403 Podocyte Biology
Authors
- Naik, Abhijit S., University of Michigan, Ann Arbor, Michigan, United States
- Fermin, Damian, University of Michigan, Ann Arbor, Michigan, United States
- Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States
- Eichinger, Felix H., University of Michigan, Ann Arbor, Michigan, United States
- Harder, Jennifer L., University of Michigan, Ann Arbor, Michigan, United States
- Mariani, Laura H., University of Michigan, Ann Arbor, Michigan, United States
- Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
Background
In kidney allografts, IGF-1 signaling was associated with reduced expression of Integrin A3, a key podocyte adhesion protein, and accelerated podocyte detachment. Insulin-like growth factor binding protein 2 (IGFBP2) and the high-temperature requirement factor A1 (HTRA1) contributed to the observed IGF-1 signaling. Podocyte specificity of HTRA1 was affirmed by single-cell RNA sequencing of healthy kidney tissue. The HTRA1 encodes a protease and makes bound IGF-1 locally bioavailable(doi.org/10.1016/s0014-5793(96)01229-x). Since 99% IGF-1 is bound, functional mutations in the HTRA1 gene could therefore perturb local IGF-1 signaling with functional consequences.
Methods
We searched for HTRA1 coding variants in the NEPTUNE cohort (n=620). Six distinct variants passed QC filtering. Each variant was then examined for its association with negative outcome (ESRD or 40% reduction in GFR). Transcriptional consequences on IGF-1 signaling of these mutations were evaluated in glomerular RNA-sequencing data.
Results
One variant was associated with a 2.7-fold increased risk of negative outcome. This relatively rare SNP (rs369149111); allele frequency-0.0248 results in a missense mutation, leading to alanine to valine change within the conserved signaling peptide (Ala20Val) region. Corresponding higher expression of IGF-1R in glomeruli as observed in patients with this variant.
Conclusion
SNP (rs369149111) is associated with glomerular disease progression. This rare allele likely interacts with glomerular IGF-1 signaling that then contributes to podocyte loss observed in glomerular diseases and transplanted kidneys. Further studies are necessary to confirm the prevalence and mechanistic implications of this HTRA1 variant
Funding
- NIDDK Support