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, wave form and beat frequency), production of nasal nitric oxide in vivo, and clinical phenotype. We have robust preliminary data 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 spokes (RS). For patients with these ciliary ultrastructural (electron microscopic, EM) defects, nasal nitric oxide (nNO) production is uniformly low (~ 20 ml/min), including patients with mutations we recently discovered by exome sequencing in novel genes that cause ODA defects (CCDC114) or ODA+IDA defects (SPAG1;HEATR2;LRRC6;&ZMYND10). We are now identifying an increasing number of PCD patients with normal ciliary ultrastructure (up to 31% of PCD patients at UNC) and 50% of those patients have biallelic mutations in DNAH11, RSPH4A, or two novel genes we recently discovered (RSPH1 &CCDC65). Over the past 3 years, we have made great progress in identifying mutations in 15 genes that cause ~60% of PCD, but we need to identify the remaining major PCD-causing genes. We are now whole exome sequencing 100 additional patients (NIH 1X0101HL115246-01 grant) by an NHLBI-supported sequencing center (Yale;Dr. R. Lifton). 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 with ciliary EM defects. 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 will also lead to discovery of "milder" genetic mutations associated with normal ciliary ultrastructure and likely some residual ciliary function. Ultimately, this will allow development of clinical genetic testing for PCD, and future studies of the role of partial loss of ciliary function in the predisposition to moe common airways diseases, such as chronic obstructive pulmonary disease.

Public Health Relevance

The overall goals of this project are to use whole exome sequencing to identify the mutations in genes that are key to the function of respiratory cilia to protect the normal lung, and the effects of genetic mutations that adversely affect ciliary functio and cause Primary Ciliary Dyskinesia (PCD), which results in life-shortening lung disease. Successful completion of this project will enable genetic testing for PCD. Long-term, we hope to develop better understanding of the underlying genetic variability that adversely modifies ciliary function, and predisposes to common airway diseases, such as chronic obstructive pulmonary disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Banks-Schlegel, Susan P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Internal Medicine/Medicine
Schools of Medicine
Chapel Hill
United States
Zip Code
Kim, Raymond H; A Hall, David; Cutz, Ernest et al. (2014) The role of molecular genetic analysis in the diagnosis of primary ciliary dyskinesia. Ann Am Thorac Soc 11:351-9
Lin, Jianfeng; Yin, Weining; Smith, Maria C et al. (2014) Cryo-electron tomography reveals ciliary defects underlying human RSPH1 primary ciliary dyskinesia. Nat Commun 5:5727
Teves, Maria E; Sears, Patrick R; Li, Wei et al. (2014) Sperm-associated antigen 6 (SPAG6) deficiency and defects in ciliogenesis and cilia function: polarity, density, and beat. PLoS One 9:e107271
Shapiro, Adam J; Weck, Karen E; Chao, Kay C et al. (2014) Cri du chat syndrome and primary ciliary dyskinesia: a common genetic cause on chromosome 5p. J Pediatr 165:858-61
Knowles, Michael R; Ostrowski, Lawrence E; Leigh, Margaret W et al. (2014) Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype. Am J Respir Crit Care Med 189:707-17
Zariwala, Maimoona A; Gee, Heon Yung; Kurkowiak, Malgorzata et al. (2013) ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6. Am J Hum Genet 93:336-45
Knowles, Michael R; Daniels, Leigh Anne; Davis, Stephanie D et al. (2013) Primary ciliary dyskinesia. Recent advances in diagnostics, genetics, and characterization of clinical disease. Am J Respir Crit Care Med 188:913-22
Sears, Patrick R; Thompson, Kristin; Knowles, Michael R et al. (2013) Human airway ciliary dynamics. Am J Physiol Lung Cell Mol Physiol 304:L170-83
Daniels, M Leigh Anne; Leigh, Margaret W; Davis, Stephanie D et al. (2013) Founder mutation in RSPH4A identified in patients of Hispanic descent with primary ciliary dyskinesia. Hum Mutat 34:1352-6
Ferkol, Thomas W; Puffenberger, Erik G; Lie, Hauw et al. (2013) Primary ciliary dyskinesia-causing mutations in Amish and Mennonite communities. J Pediatr 163:383-7

Showing the most recent 10 out of 29 publications