Expression of a Truncated Form of ODAD1 Associated with an Unusually Mild Primary Ciliary Dyskinesia Phenotype.

Lawrence E Ostrowski,Margaret W Leigh,Hong Dang,Weining Yin,Ximena M Bustamante-Marin,Maimoona A Zariwala,Nicole A Capps,Leigh Anne Daniels,Michael R Knowles,Friedhelm Hildebrandt,Patrick R Sears,Kelli M Sullivan,Amanda J Smith

doi:10.3390/ijms23031753

Abstract

Primary ciliary dyskinesia (PCD) is a rare lung disease caused by mutations that impair the function of motile cilia, resulting in chronic upper and lower respiratory disease, reduced fertility, and a high prevalence of situs abnormalities. The disease is genetically and phenotypically heterogeneous, with causative mutations in > 50 genes identified, and clinical phenotypes ranging from mild to severe. Absence of ODAD1 (CCDC114), a component of the outer dynein arm docking complex, results in a failure to assemble outer dynein arms (ODAs), mostly immotile cilia, and a typical PCD phenotype. We identified a female (now 34 years old) with an unusually mild clinical phenotype who has a homozygous non-canonical splice mutation (c.1502+5G>A) in ODAD1. To investigate the mechanism for the unusual phenotype, we performed molecular and functional studies of cultured nasal epithelial cells. We demonstrate that this splice mutation results in the expression of a truncated protein that is attached to the axoneme, indicating that the mutant protein retains partial function. This allows for the assembly of some ODAs and a significant level of ciliary activity that may result in the atypically mild clinical phenotype. The results also suggest that partial restoration of ciliary function by therapeutic agents could lead to significant improvement of disease symptoms.

Highlights

Primary ciliary dyskinesia (PCD) is a rare disease usually inherited in an autosomal recessive manner and characterized by chronic and recurrent lung infections leading to bronchiectasis, sinusitis, otitis media, reduced fertility, and laterality defects [1,2]
Probing of replicate blots for DNAI1, a component of the outer dynein arms (ODAs), was positive in ciliary axonemes from UNC78, providing further evidence for the assembly of some complete ODA (Figure S3). These results demonstrate that the c.1502+5G>A mutation results in the production of a truncated ODAD1 protein that is incorporated into the ciliary axoneme and retains partial function
Individuals with PCD suffer from a variety of symptoms including recurrent lung, sinus and ear infections that are the result of defective mucociliary clearance (MCC), due to mutations that impair the biogenesis and/or function of motile cilia

Summary

Introduction

Primary ciliary dyskinesia (PCD) is a rare disease usually inherited in an autosomal recessive manner and characterized by chronic and recurrent lung infections leading to bronchiectasis, sinusitis, otitis media, reduced fertility, and laterality defects [1,2]. Much of the morbidity and mortality in PCD is caused by defective mucociliary clearance (MCC) in the airways, resulting in frequent pulmonary infections and the development of bronchiectasis [5]. A study comparing clinical features of bronchiectasis of PCD with bronchiectasis caused by other etiologies revealed that compared to alpha-1 antitrypsin deficiency (AATD), common variable immunodeficiency (CVI), and idiopathic bronchiectasis, subjects with PCD had worse lung function (forced expiratory volume in 1 s; FEV1) and developed disease at an earlier age [6].

Methods

Results

Conclusion