Pathogenesis of Primary Ciliary Dyskinesia (PCD) Lung Disease
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|ClinicalTrials.gov Identifier: NCT00807482|
Recruitment Status : Recruiting
First Posted : December 12, 2008
Last Update Posted : May 14, 2021
|Condition or disease|
A key component of lung defense is the efficiency of mucociliary clearance (MCC).
Primary ciliary dyskinesia (PCD) is a human genetic disorder with defective MCC. This ongoing project is designed to identify additional disease-causing mutations in PCD, and correlate the molecular etiologies with the ciliary phenotype (ultrastructure, wave form and beat frequency). We have recently shown that the normal human cilium has a distinctive waveform, i.e. beats in-plane with defined curvatures and amplitudes for the effective (forward) and recovery stroke. We hypothesize that discrete sets of genes contribute to the structure and function of the ciliary outer dynein arm (ODA), inner dynein arm (IDA), and central pair (CP) and radial spoke (RS) complex (CP/RS), and that we can identify novel genetic mutations in different structural components of the cilium that will have different effects on ciliary ultrastructure, wave form, and beat frequency. Importantly, we are now able to identify patients with PCD who do not have hallmark diagnostic ultrastructural defects, based on distinctive clinical phenotypes (including situs inversus), low or borderline nasal NO production, and abnormal ciliary motility. Identification of PCD patients with normal ciliary ultrastructure (~16% of PCD patients at UNC) offers the opportunity to discover mutations in genes that cause functional, but not ultrastructural, defects (such as DNAH11), and to correlate those mutations with ciliary waveform abnormalities. Over the past 4 years, we have made great progress in identifying mutations in 2 genes (DNAI1 and DNAH5) that cause ~60% of ODA defects in PCD, and ~35% of PCD overall. We will extend our search for disease causing mutations in PCD, using several different approaches, including studies of additional candidate genes, (guided by ultrastructure), plus insights from ciliary proteomics, and family-based studies. Taken together, these studies will provide new insights regarding the relationship of mutations in specific genes to ciliary ultrastructural and functional defects. These studies will not only greatly enhance our ability to diagnose PCD, but will also lead to discovery of "milder" genetic mutations associated with normal ciliary ultrastructure, and likely some residual ciliary function. Ultimately, this will allow future studies of the role of partial loss of ciliary function in the predisposition to more common airways diseases, such as chronic bronchitis and chronic obstructive pulmonary disease.
|Study Type :||Observational|
|Estimated Enrollment :||1800 participants|
|Official Title:||Diagnostic and Clinical Characterization of Patients With Unusual Genetic Disorders of the Airways|
|Study Start Date :||January 2004|
|Estimated Primary Completion Date :||April 2023|
|Estimated Study Completion Date :||April 2023|
People who have been definitively diagnosed with primary ciliary dyskinesia (PCD).
- This is not an interventional study [ Time Frame: This is not an interventional study ]Not applicable. This is not an interventional study.
Biospecimen Retention: Samples With DNA
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Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00807482
|Principal Investigator:||Michael R. Knowles, MD||University of North Carolina, Chapel Hill|