# Functional Studies of Novel Genes Mutated in Primary Ciliary Dyskinesia II: Genotype to Phenotype

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $673,135

## Abstract

Project Summary/Abstract
In primary ciliary dyskinesia (PCD), mutations in proteins that play a role in the proper assembly or function of
the cilia result in defective ciliary beating, which leads to greatly reduced or absent mucociliary clearance
(MCC). The lack of effective MCC results in chronic lung infections, bronchiectasis, chronic sinusitis, and otitis
media. Although all PCD subjects have a similar clinical phenotype, the disease is heterogeneous in severity,
with some patients having mild symptoms, while others develop severe bronchiectasis. Because mutations in
many of the genes that cause PCD have been shown to result in essentially immotile cilia and are expected to
result in no MCC, it is not obvious why there exists such a wide range of clinical phenotypes. Our hypothesis is
that much of the heterogeneity of disease severity observed in PCD patients is a result of genetic
heterogeneity, and that mutations in different genes result in varying levels of residual MCC and consequently,
varying severity of disease. Further, we hypothesize that different mutations in the same gene can also result
in different levels of ciliary impairment, MCC, and disease severity. Finally, we propose that understanding the
mechanistic basis for the differences in disease phenotype will provide targets and opportunities to develop
new, personalized treatments for this rare disease. The specific aims are:
 1. To investigate the expression and function of genes and proteins, including CFAP57 and PCDP1,
 mutations of which have been newly shown to cause PCD.
 Using patient derived human nasal epithelial (HNE) cells and/or induced pluripotent stem (iPS) cells, we
 will investigate the effect of the mutations at the level of the protein, ciliary function (waveform and beat
 frequency), and mucociliary transport (MCT) in vitro.
 2. To investigate genotype/phenotype relationships in patient derived iPS cells.
 We will examine the functional consequences of mutations in different genes (CFAP57, PCDP1, RSPH1,
 CCDC39, and DNAI1) and of different mutations in the same gene (SPAG1, CCDC114, DNAH5) in iPS
 cells from PCD patients.
 3. To investigate the pathogenesis of disease in a mouse model with a deletion of Ccdc39.
 We will compare the effects of an inducible deletion of Ccdc39 to an inducible of Dnaic1.
 4. To investigate the relationship between genotype, MCC, and clinical phenotype in vivo.
 MCC will be measured in PCD subjects with RSPH1 mutations and compared to PCD subjects with
 mutations in other genes (e.g., DNAI1, DNAH5). In addition, MCC will be measured after administration of
 a beta-agonist to determine if MCC can be stimulated in the RSPH1 subjects.

## Key facts

- **NIH application ID:** 9887916
- **Project number:** 2R01HL117836-06
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** LAWRENCE E OSTROWSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $673,135
- **Award type:** 2
- **Project period:** 2013-08-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9887916

## Citation

> US National Institutes of Health, RePORTER application 9887916, Functional Studies of Novel Genes Mutated in Primary Ciliary Dyskinesia II: Genotype to Phenotype (2R01HL117836-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9887916. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*