Pathogenesis of Primary Ciliary Dyskinesia (PCD) Lung Disease

Study Overview
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Brief Summary
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The overall short-term goals of this project include the following: 1) identify the genes that are key to the function of respiratory cilia to protect the normal lung; and 2) the effects of genetic mutations that adversely affect ciliary function and cause primary ciliary dyskinesia (PCD), which results in life-shortening lung disease. The long-term goal of this project is to develop better understanding of the underlying genetic variability that adversely modifies ciliary function, and predisposes to common airway diseases, such as asthma and chronic obstructive pulmonary disease.

Detailed Description
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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.

Official Title
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Diagnostic and Clinical Characterization of Patients With Unusual Genetic Disorders of the Airways

Conditions
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Kartagener Syndrome

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who have a high suspicion for the diagnosis of PCD, based on clinical features Healthy Volunteers who have a family member with confirmed PCD.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| 1<br>People who have been definitively diagnosed with primary ciliary dyskinesia (PCD). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| This is not an interventional study | Not applicable. This is not an interventional study. | This is not an interventional study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary Ciliary Dyskinesia, Mucociliary Clearance, Genetic Mutation