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Pathogenesis of Primary Ciliary Dyskinesia (PCD) Lung Disease

This study is currently recruiting participants.
Verified September 2017 by University of North Carolina, Chapel Hill
Sponsor:
ClinicalTrials.gov Identifier:
NCT00807482
First Posted: December 12, 2008
Last Update Posted: September 14, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill
  Purpose
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.

Condition
Kartagener Syndrome

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Diagnostic and Clinical Characterization of Patients With Unusual Genetic Disorders of the Airways

Resource links provided by NLM:


Further study details as provided by University of North Carolina, Chapel Hill:

Primary Outcome Measures:
  • 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
Blood samples, buckle scrape, semen, and scrape biopsy of nasal cells

Estimated Enrollment: 1800
Study Start Date: January 2004
Estimated Study Completion Date: April 2021
Estimated Primary Completion Date: April 2021 (Final data collection date for primary outcome measure)
Groups/Cohorts
1
People who have been definitively diagnosed with primary ciliary dyskinesia (PCD).

Detailed Description:

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.

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
Patients who have a high suspicion for the diagnosis of PCD, based on clinical features.
Criteria

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.

  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00807482


Locations
United States, North Carolina
The University of North Carolina at Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Michael R. Knowles, MD    919-966-6780    knowles@med.unc.edu   
Contact: Beth Godwin, BA    919-966-6780    godwine@med.unc.edu   
Sponsors and Collaborators
University of North Carolina, Chapel Hill
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Michael R. Knowles, MD University of North Carolina, Chapel Hill
  More Information

Additional Information:
Publications:
Zariwala MA, Gee HY, Kurkowiak M, Al-Mutairi DA, Leigh MW, Hurd TW, Hjeij R, Dell SD, Chaki M, Dougherty GW, Adan M, Spear PC, Esteve-Rudd J, Loges NT, Rosenfeld M, Diaz KA, Olbrich H, Wolf WE, Sheridan E, Batten TF, Halbritter J, Porath JD, Kohl S, Lovric S, Hwang DY, Pittman JE, Burns KA, Ferkol TW, Sagel SD, Olivier KN, Morgan LC, Werner C, Raidt J, Pennekamp P, Sun Z, Zhou W, Airik R, Natarajan S, Allen SJ, Amirav I, Wieczorek D, Landwehr K, Nielsen K, Schwerk N, Sertic J, Köhler G, Washburn J, Levy S, Fan S, Koerner-Rettberg C, Amselem S, Williams DS, Mitchell BJ, Drummond IA, Otto EA, Omran H, Knowles MR, Hildebrandt F. ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6. Am J Hum Genet. 2013 Aug 8;93(2):336-45. doi: 10.1016/j.ajhg.2013.06.007. Epub 2013 Jul 25.
Noone PG, Zariwala MB,Knowles MR. Primary Ciliary Dyskinesia. In: Principles of Molecular Medicine. Editors: MS Runge and C Patterson, 2nd Edition, Humana Press, Totowa, NJ, pp 239-250, 2006.

Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT00807482     History of Changes
Other Study ID Numbers: 98-1015
5R01HL071798 ( U.S. NIH Grant/Contract )
First Submitted: December 11, 2008
First Posted: December 12, 2008
Last Update Posted: September 14, 2017
Last Verified: September 2017

Keywords provided by University of North Carolina, Chapel Hill:
Primary Ciliary Dyskinesia
Mucociliary Clearance
Genetic Mutation

Additional relevant MeSH terms:
Ciliary Motility Disorders
Kartagener Syndrome
Respiratory Tract Diseases
Otorhinolaryngologic Diseases
Ciliopathies
Abnormalities, Multiple
Congenital Abnormalities
Genetic Diseases, Inborn
Bronchiectasis
Bronchial Diseases
Respiratory System Abnormalities
Dextrocardia
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Situs Inversus