# Pathogenesis of PCD Lung Disease

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $616,952

## Abstract

Abstract
Primary ciliary dyskinesia (PCD) is a recessive, genetically heterogeneous disorder with defective mucociliary
clearance. This ongoing project is designed to identify additional disease-causing mutations in PCD using
whole exome sequencing, and then to correlate the molecular etiologies with the ciliary phenotype
(ultrastructure, beat frequency and wave form), production of nasal nitric oxide in vivo, and clinical phenotype.
We have published extensive data that discrete sets of genes contribute to the structure and function of the
ciliary outer dynein arm (ODA), inner dynein arm (IDA), and “9+2” axonemal structure. For patients with these
ciliary ultrastructural defects, nasal nitric oxide (nNO) production is low (~ 20 ml/min), including patients with
mutations we recently discovered by exome sequencing in a novel gene that causes ODA defects (C11orf70).
We are also identifying an increasing number of PCD patients with normal or non-diagnostic ciliary
ultrastructure (up to 32% of PCD patients at UNC), including two novel genes we recently discovered
(CFAP221/PCDP1 & CFAP57/WDR65)). Over the past 4 years, we have made great progress by identifying
mutations in 14 of the 39 genes that cause 65-70% of PCD, but we need to identify additional PCD-causing
genes. We are now whole exome sequencing 100 additional patients at an NIH-supported sequencing center
(Yale; Dr. Shrikant Mane; 2UM1HG006504-05). This exome sequencing project will extend our search for
disease-causing mutations by including patients who have a PCD-compatible clinical phenotype, but with nNO
values that are higher than typical for PCD patients. Followup studies will be performed at UNC to validate
novel gene discoveries, and characterize gene/protein expression and function in human ciliated airway cells.
Taken together, these studies will provide new insights regarding the relationship of mutations in novel genes
to ciliary ultrastructural and functional defects. These studies will not only greatly enhance our ability to
diagnose PCD, but may also lead to discovery of "milder" genetic mutations associated with normal ciliary
ultrastructure, and likely some residual ciliary function. Ultimately, results from this proposal will improve
clinical genetic testing for PCD, and enable earlier diagnosis, clinical monitoring, and improved outcomes for
patients with PCD.

## Key facts

- **NIH application ID:** 9922334
- **Project number:** 5R01HL071798-15
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Michael R Knowles
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $616,952
- **Award type:** 5
- **Project period:** 2004-01-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922334

## Citation

> US National Institutes of Health, RePORTER application 9922334, Pathogenesis of PCD Lung Disease (5R01HL071798-15). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9922334. Licensed CC0.

---

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