# Identification of Kidney Disease Modifier Genes in Mouse and Human Alport Syndrome

> **NIH NIH R01** · JACKSON LABORATORY · 2022 · $457,780

## Abstract

PROJECT SUMMARY/ABSTRACT
Alport syndrome is a human hereditary glomerulonephritis, which in most cases, results in end-stage renal
disease. It is the most common inherited glomerular disease leading to renal failure and is caused by mutations
in any one of the genes encoding a3, a4, or a5 chains of type IV collagen (COL4A3, COL4A4, and COL4A5,
respectively). There is large variation in the age of onset and severity of the disease, even between patients with
similar mutations. Studies in mice have shown that the renal phenotype is highly dependent on the genetic
background. It is widely accepted that modifier genes contribute to this variation, which could represent a source
of novel therapeutic targets in Alport syndrome and other renal diseases. We identified human-relevant modifier
genes in a small cohort of genetically diverse mice with a Col4a5 mutation (leading to X-linked Alport syndrome
(XLAS)) and validated that decreased expression of one of these genes, Fmn1, leads to a less severe renal
phenotype. We further found that two of the candidate modifier genes (Pik3r1 and Dgke) modulate other forms
of kidney disease, including diabetic nephropathy and hematolytic urea syndrome. In this application we will
discover novel candidate modifier genes of XLAS by high-resolution genetic mapping in a large
genetically diverse XLAS mouse cohort and confirm the translational relevance of the modifiers in
humans. The functional impact and causality of the modifier genes will be assessed in preclinical mouse
models of XLAS and other forms of kidney disease. We will generate a large, genetically diverse XLAS
mouse population that, combined with our previous population, will allow us gene-resolution mapping of modifier
loci (Aim 1). Whole exome sequencing and targeted testing for the detection of the most likely candidate modifier
genes in human XLAS pedigrees will be conducted to confirm the translational relevance of the candidate
modifier genes found in our mouse studies (Aim 2). We will use available knockout resources and/or CRISPR-
Cas9 gene editing to test causality of as many as five candidate genes in the XLAS mouse model (Aim 3A). We
will further test these modifier genes for causality in mouse models of two common forms of kidney disease:
diabetic nephropathy and focal segmental glomerulosclerosis syndrome (Aim 3B). Identification of the genes
responsible for the onset and severity of disease will provide meaningful insights into understanding the
molecular events underlying the pathogenesis of kidney disease and provide the basis for developing novel
therapeutic strategies.

## Key facts

- **NIH application ID:** 10341489
- **Project number:** 1R01DK131019-01
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** Ronny Korstanje
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $457,780
- **Award type:** 1
- **Project period:** 2022-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10341489

## Citation

> US National Institutes of Health, RePORTER application 10341489, Identification of Kidney Disease Modifier Genes in Mouse and Human Alport Syndrome (1R01DK131019-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10341489. Licensed CC0.

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