PDF(Pubmed)
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.
摘要：
原发性纤毛运动障碍（PCD）是由活动纤毛功能和/或结构缺陷引起的遗传异质性疾病。外动力蛋白臂对接复合物亚基1(ODAD1)是外动力蛋白臂对接复合物(ODA-DC)的重要组成部分。迄今为止,已经报道了13种可能的ODAD1致病突变。然而,ODAD1突变的发病机制仍然难以捉摸.为了探讨本研究中发现的和以前报道的ODAD1剪接位点突变的发病机制，进行了分子和功能分析。全外显子组测序显示PCD患者ODAD1的复合突变（c.71-2A>C;c.598-2A>C），c.598-2A>C是一种新的突变，导致两个突变转录本。ODAD1中的复合突变（c.71-2A>C;c.598-2A>C）导致异常剪接，导致缺乏野生型ODAD1和睫状轴突外动力蛋白臂的缺陷，导致纤毛搏动频率降低。此外，我们证明由ODAD1剪接位点突变产生的截短蛋白可以保留部分功能并抑制野生型ODAD1和ODAD3之间的相互作用.这项研究的结果扩大了PCD的突变和临床谱，为遗传咨询提供更多证据，并为基于基因的PCD治疗策略提供新的见解。
