# Discover and functionally characterize full-penetrance causes of nephrosis / FSGS

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2021 · $398,250

## Abstract

ABSTRACT
Discover and functionally characterize full-penetrance causes of nephrosis/FSGS.
Chronic kidney diseases (CKD) take one of the highest tolls on human health, and their prevalence
continuously rises. Steroid-resistant nephrotic syndrome (SRNS) is the 2nd most frequent cause of CKD
before 25 yrs. By focal segmental glomerulosclerosis (FSGS) it inevitably leads to CKD with a 33% recurrence
risk in a renal transplant. The pathogenesis of SRNS is unknown and no curative treatment is available. For
SRNS, the primary causes (etiology) and disease mechanisms (pathogenesis) have been a conundrum for
decades. However, identification of full-penetrance single-gene causes of NS (e.g. podocin) has implicated
the renal glomerular podocyte at the center of the pathogenesis. Within the 2 previous R01 funding periods we:
1) Identified by whole exome sequencing 34 of the 50 currently known single-gene causes of NS and
functionally characterized the related disease mechanisms; 2) Discovered that the encoded proteins
cluster in protein complexes thereby defining novel disease pathways for SRNS (e.g., RhoA/Rac1/Cdc42
signaling); 3) Delineated genotype-phenotype correlations with actionable implications for personalized
disease management; 4) Modeled the related disease mechanisms in the `podocyte migration assay',
zebrafish & mouse models; 5) Revealed `personalized treatment' options for specific patients (e.g. CoQ10
in COQ6 or ADCK4 mutations); 6) Demonstrated in a world-wide cohort that ~30% of SRNS (<25 yrs) is
caused by single-gene mutations, thereby permitting genetic mechanistic studies and personalized
medicine for patients with SRNS ; 7) Discovered the first genetic causes of steroid-dependent NS (6
genes), converging on RhoA regulation. These genetic discoveries made the study of SRNS accessible to
genetic approaches of `precision medicine', enabling genetic diagnostics, the study of `personalized'
disease mechanisms, and treatment approaches. We, therefore will pursue the following Specific Aims:
SA1. Discover the missing single-gene causes of SRNS by WES in ~1,000 SRNS families.
SA2. Functionally characterize newly identified single-gene causes of SRNS/SSNS to delineate the
 pathogenesis and study `personalized' genotype-phenotype and genotype-treatment
correlations.
SA3. Perform small molecule screens in CRISPR k.o. models of novel SRNS genes identified, using
 established `podocyte migration assay' and zebrafish models, to discover the first drugs for
SRNS.
SA4. Study the 6 novel single-gene causes that we discovered in steroid-dependent NS to converge
 on RhoA regulation delineate mechanisms of steroid and other direct drug effects on podocytes.

## Key facts

- **NIH application ID:** 10247519
- **Project number:** 5R01DK076683-16
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** FRIEDHELM HILDEBRANDT
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $398,250
- **Award type:** 5
- **Project period:** 2007-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247519

## Citation

> US National Institutes of Health, RePORTER application 10247519, Discover and functionally characterize full-penetrance causes of nephrosis / FSGS (5R01DK076683-16). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247519. Licensed CC0.

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