ODAD1 variants resulting from splice-site mutations retain partial function and cause primary ciliary dyskinesia with outer dynein arm defects

Nannan Zhou; Weilin Liang; Yanzhu Zhang; Guoli Quan; Ting Li; Siqing Huang; Yating Huo; Haiyan Cui; Yuanxiong Cheng

doi:10.3389/fgene.2023.1270278

ODAD1 variants resulting from splice-site mutations retain partial function and cause primary ciliary dyskinesia with outer dynein arm defects

Front Genet. 2023 Oct 31:14:1270278. doi: 10.3389/fgene.2023.1270278. eCollection 2023.

Authors

Nannan Zhou¹, Weilin Liang¹, Yanzhu Zhang¹, Guoli Quan¹, Ting Li¹, Siqing Huang¹, Yating Huo¹, Haiyan Cui¹, Yuanxiong Cheng¹

Affiliation

¹ Department of Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.

Abstract

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by defects in motile ciliary function and/or structure. Outer dynein arm docking complex subunit 1 (ODAD1) is an important component of the outer dynein arm docking complex (ODA-DC). To date, 13 likely pathogenic mutations of ODAD1 have been reported. However, the pathogenesis of ODAD1 mutations remains elusive. To investigate the pathogenesis of splice-site mutations in ODAD1 discovered in this study and those reported previously, molecular and functional analyses were performed. Whole-exome sequencing revealed a compound mutation in ODAD1 (c.71-2A>C; c.598-2A>C) in a patient with PCD, with c.598-2A>C being a novel mutation that resulted in two mutant transcripts. The compound mutation in ODAD1 (c.71-2A>C; c.598-2A>C) led to aberrant splicing that resulted in the absence of the wild-type ODAD1 and defects of the outer dynein arm in ciliary axonemes, causing a decrease in ciliary beat frequency. Furthermore, we demonstrated that the truncated proteins resulting from splice-site mutations in ODAD1 could retain partial function and inhibit the interaction between wild-type ODAD1 and ODAD3. The results of this study expand the mutational and clinical spectrum of PCD, provide more evidence for genetic counseling, and offer new insights into gene-based therapeutic strategies for PCD.

Keywords: CCDC114; ODAD1; outer dynein arm; outer dynein arm docking complex; primary ciliary dyskinesia; truncated protein.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work is supported by the President Funding of the Third Affiliated Hospital of Southern Medical University (YM202211), the Natural Science Foundation of Guangdong Province (2020A1515010458), and the Scientific and Technological Project of Henan Science and Technology Department (212102310784), which only provided funding support and did not participate in specific research.