# Novel genetics, pathobiology and therapy of nephronophthisis-related ciliopathies

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

## Abstract

1. ABSTRACT
Novel genetics, pathobiology, and therapy of nephronophthisis-related ciliopathies (NPHP-RC).
Nephronophthisis-related ciliopathies (NPHP-RC) are recessive cystic kidney diseases that cause chronic
kidney disease (CKD) in the first 30 years of life. They can be associated with retinal degeneration, liver
fibrosis, skeletal and brain malformations. No treatment exists for NPHP-RC. Using genetic mapping and
whole exome sequencing, we discovered, functionally characterized and published 46 of the ~100 genes
currently known to cause NPHP-RC, if mutated. Gene discovery lead to the following insights: i) the
“ciliopathy theory” of cystic kidney diseases; ii) discovery that the pathogenesis of NPHP-RC involves
mechanisms of non-canonical Wnt signaling, planar cell polarity, sonic hedgehog signaling, aspects of cell
cycle regulation; iii) generation of mouse and zebrafish models of NPHP-RC; iv) , and v) the realization that
syndromic developmental forms of NPHP-RC are primarily caused by null mutations, whereas degene-
rative forms are preferentially caused by hypomorphic mutations in the same NPHP-RC genes. We also
showed that with ~100 NPHP-RC genes identified, the encoded NPHP-RC proteins cluster within specific
centrosomal/ciliary protein interaction complexes that partially correlate with disease phenotypes.
We developed a high-throughput sequencing system that allows rapid mutation analysis of all ~100 known
NPHP-RC genes, demonstrating in a worldwide cohort of 1,540 families with NPHP-RC that mutations in
known genes only explain ~50% of all cases and that many additional NPHP-RC genes must exist. In the
last 3 years, we discovered, characterized and published 11 novel NPHP-RC genes.
Very recently, by identifying recessive mutations in MAP7D3 and TTC28 as causing NPHP-RC, we
revealed centrosomal/ciliary protein interaction clusters relevant for ciliary length control as related to
the pathogenesis of NPHP-RC.
To discover the missing NPHP-RC genes, to delineate the associated signaling mechanisms, and to generate
develop therapeutic options using animal models, we now propose to:
SA1. Identify and functionally characterize the missing components of NPHP-related ciliopathies by
whole exome/genome sequencing, CNV and mRNAseq analysis in ~1,500 families with NPHP-RC.
SA2. Characterize disease mechanisms for the newly identified NPHP-RC genes MAP7D3 and TTC28
that participate in a shared centrosomal module.
SA3. Utilize zebrafish models for allele validation, to delineate pathogenic pathways, and to develop
first treatment options for NPHP-RC.
1

## Key facts

- **NIH application ID:** 10082447
- **Project number:** 5R01DK068306-17
- **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:** 2004-06-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10082447

## Citation

> US National Institutes of Health, RePORTER application 10082447, Novel genetics, pathobiology and therapy of nephronophthisis-related ciliopathies (5R01DK068306-17). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10082447. Licensed CC0.

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