Pathogenesis of Primary Ciliary Dyskinesia (PCD) Lung Disease

Kartagener Syndrome Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00807482
• Other study ID #: 98-1015
• Secondary ID: 5R01HL071798
• Status: Recruiting
• Start date: January 2004
• Est. completion date: April 2025

Study information

• Verified date: April 2023
• Source: University of North Carolina, Chapel Hill
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1800
• Est. completion date: April 2025
• Est. primary completion date: April 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Ciliary Motility Disorders
• Kartagener Syndrome

Locations

Country	Name	City	State
United States	The University of North Carolina at Chapel Hill	Chapel Hill	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
University of North Carolina, Chapel Hill	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (18)

Austin-Tse C, Halbritter J, Zariwala MA, Gilberti RM, Gee HY, Hellman N, Pathak N, Liu Y, Panizzi JR, Patel-King RS, Tritschler D, Bower R, O'Toole E, Porath JD, Hurd TW, Chaki M, Diaz KA, Kohl S, Lovric S, Hwang DY, Braun DA, Schueler M, Airik R, Otto EA — View Citation

Berg JS, Evans JP, Leigh MW, Omran H, Bizon C, Mane K, Knowles MR, Weck KE, Zariwala MA. Next generation massively parallel sequencing of targeted exomes to identify genetic mutations in primary ciliary dyskinesia: implications for application to clinical — View Citation

Daniels ML, Leigh MW, Davis SD, Armstrong MC, Carson JL, Hazucha M, Dell SD, Eriksson M, Collins FS, Knowles MR, Zariwala MA. Founder mutation in RSPH4A identified in patients of Hispanic descent with primary ciliary dyskinesia. Hum Mutat. 2013 Oct;34(10) — View Citation

Ferkol TW, Puffenberger EG, Lie H, Helms C, Strauss KA, Bowcock A, Carson JL, Hazucha M, Morton DH, Patel AC, Leigh MW, Knowles MR, Zariwala MA. Primary ciliary dyskinesia-causing mutations in Amish and Mennonite communities. J Pediatr. 2013 Aug;163(2):38 — View Citation

Funkhouser WK 3rd, Niethammer M, Carson JL, Burns KA, Knowles MR, Leigh MW, Zariwala MA, Funkhouser WK Jr. A new tool improves diagnostic test performance for transmission em evaluation of axonemal dynein arms. Ultrastruct Pathol. 2014 Aug;38(4):248-55. d — View Citation

Hjeij R, Lindstrand A, Francis R, Zariwala MA, Liu X, Li Y, Damerla R, Dougherty GW, Abouhamed M, Olbrich H, Loges NT, Pennekamp P, Davis EE, Carvalho CM, Pehlivan D, Werner C, Raidt J, Kohler G, Haffner K, Reyes-Mugica M, Lupski JR, Leigh MW, Rosenfeld M — View Citation

Hornef N, Olbrich H, Horvath J, Zariwala MA, Fliegauf M, Loges NT, Wildhaber J, Noone PG, Kennedy M, Antonarakis SE, Blouin JL, Bartoloni L, Nusslein T, Ahrens P, Griese M, Kuhl H, Sudbrak R, Knowles MR, Reinhardt R, Omran H. DNAH5 mutations are a common — View Citation

Kennedy MP, Noone PG, Leigh MW, Zariwala MA, Minnix SL, Knowles MR, Molina PL. High-resolution CT of patients with primary ciliary dyskinesia. AJR Am J Roentgenol. 2007 May;188(5):1232-8. doi: 10.2214/AJR.06.0965. — View Citation

Kennedy MP, Omran H, Leigh MW, Dell S, Morgan L, Molina PL, Robinson BV, Minnix SL, Olbrich H, Severin T, Ahrens P, Lange L, Morillas HN, Noone PG, Zariwala MA, Knowles MR. Congenital heart disease and other heterotaxic defects in a large cohort of patien — View Citation

Knowles MR, Leigh MW, Ostrowski LE, Huang L, Carson JL, Hazucha MJ, Yin W, Berg JS, Davis SD, Dell SD, Ferkol TW, Rosenfeld M, Sagel SD, Milla CE, Olivier KN, Turner EH, Lewis AP, Bamshad MJ, Nickerson DA, Shendure J, Zariwala MA; Genetic Disorders of Mucociliary Clearance Consortium. Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia. Am J Hum Genet. 2013 Jan 10;92(1):99-106. doi: 10.1016/j.ajhg.2012.11.003. Epub 2012 Dec 20. — View Citation

Knowles MR, Ostrowski LE, Loges NT, Hurd T, Leigh MW, Huang L, Wolf WE, Carson JL, Hazucha MJ, Yin W, Davis SD, Dell SD, Ferkol TW, Sagel SD, Olivier KN, Jahnke C, Olbrich H, Werner C, Raidt J, Wallmeier J, Pennekamp P, Dougherty GW, Hjeij R, Gee HY, Otto — View Citation

Leigh MW, Hazucha MJ, Chawla KK, Baker BR, Shapiro AJ, Brown DE, Lavange LM, Horton BJ, Qaqish B, Carson JL, Davis SD, Dell SD, Ferkol TW, Atkinson JJ, Olivier KN, Sagel SD, Rosenfeld M, Milla C, Lee HS, Krischer J, Zariwala MA, Knowles MR. Standardizing — View Citation

Lie H, Zariwala MA, Helms C, Bowcock AM, Carson JL, Brown DE 3rd, Hazucha MJ, Forsen J, Molter D, Knowles MR, Leigh MW, Ferkol TW. Primary ciliary dyskinesia in Amish communities. J Pediatr. 2010 Jun;156(6):1023-1025. doi: 10.1016/j.jpeds.2010.01.054. Epu — View Citation

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.

Tarkar A, Loges NT, Slagle CE, Francis R, Dougherty GW, Tamayo JV, Shook B, Cantino M, Schwartz D, Jahnke C, Olbrich H, Werner C, Raidt J, Pennekamp P, Abouhamed M, Hjeij R, Kohler G, Griese M, Li Y, Lemke K, Klena N, Liu X, Gabriel G, Tobita K, Jaspers M — View Citation

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, Lovri — View Citation

Zariwala MA, Knowles MR, Omran H. Genetic defects in ciliary structure and function. Annu Rev Physiol. 2007;69:423-50. doi: 10.1146/annurev.physiol.69.040705.141301. — View Citation

Zariwala MA, Leigh MW, Ceppa F, Kennedy MP, Noone PG, Carson JL, Hazucha MJ, Lori A, Horvath J, Olbrich H, Loges NT, Bridoux AM, Pennarun G, Duriez B, Escudier E, Mitchison HM, Chodhari R, Chung EM, Morgan LC, de Iongh RU, Rutland J, Pradal U, Omran H, Am — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	This is not an interventional study	Not applicable. This is not an interventional study.	This is not an interventional study