Wan Feng, Yu Lan, Qu Xiaowei, Xia Yanqing, Feng Ke, Zhang Lei, Zhang Na, Zhao Guihua, Zhang Cuilian, Guo Haibin
The Reproductive Medicine Center, Henan Provincial People's Hospital, Zhengzhou, China.
The Reproductive Medicine Center, People's Hospital of Zhengzhou University, Zhengzhou, China.
J Cell Mol Med. 2023 Oct;27(20):3107-3116. doi: 10.1111/jcmm.17881. Epub 2023 Aug 3.
Primary ciliary dyskinesia (PCD) is a rare autosomal-recessive disease manifested with recurrent infections of respiratory tract and infertility. DNAAF3 is identified as a novel gene associated with PCD and different mutations in DNAAF3 results in different clinical features of PCD patients, such as situs inversus, sinusitis and bronchiectasis. However, the sperm phenotypic characteristics of PCD males are generally poorly investigated. Our reproductive medicine centre received a case of PCD patient with infertility, who presented with sinusitis, recurrent infections of the lower airway and severe asthenozoospermia; However, no situs inversus was found in the patient. A novel homozygous mutation in DNAAF3(c.551T>A; p.V184E) was identified in the PCD patient by whole-exome sequencing. Subsequent Sanger sequencing further confirmed that the DNAAF3 had a homozygous missense variant in the fifth exon. Transmission electron microscopy and immunostaining analysis of the sperms from the patient showed a complete absence of outer dynein arms and partial absence of inner dynein arms, which resulted in the reduction in sperm motility. However, this infertility was overcome by intracytoplasmic sperm injections, as his wife achieved successful pregnancy. These findings showed that the PCD-associated pathogenic mutation within DNAAF3 also causes severe asthenozoospermia and male infertility ultimately due to sperm flagella axoneme defect in humans. Our study not only contributes to understand the sperm phenotypic characteristics of patients with DNAAF3 mutations but also expands the spectrum of DNAAF3 mutations and may contribute to the genetic diagnosis and therapy for infertile patient with PCD.
原发性纤毛运动障碍（PCD）是一种罕见的常染色体隐性疾病，表现为反复呼吸道感染和不孕。DNAAF3被鉴定为与PCD相关的新基因，DNAAF3中的不同突变导致PCD患者出现不同的临床特征，如内脏反位、鼻窦炎和支气管扩张。然而，PCD男性患者的精子表型特征通常研究较少。我们生殖医学中心接诊了一例因不孕前来就诊的PCD患者，该患者患有鼻窦炎、下呼吸道反复感染和严重的弱精子症；然而，患者未发现内脏反位。通过全外显子组测序在该PCD患者中鉴定出DNAAF3的一个新的纯合突变（c.551T>A；p.V184E）。随后的桑格测序进一步证实DNAAF3在第五外显子中有一个纯合错义变异。对该患者精子的透射电子显微镜和免疫染色分析显示完全没有外动力蛋白臂且部分没有内动力蛋白臂，这导致精子活力降低。然而，通过胞浆内单精子注射克服了这种不孕情况，因为他的妻子成功怀孕。这些发现表明，DNAAF3内与PCD相关的致病突变最终也会由于人类精子鞭毛轴丝缺陷导致严重的弱精子症和男性不育。我们的研究不仅有助于了解DNAAF3突变患者的精子表型特征，还扩展了DNAAF3突变谱，可能有助于PCD不孕患者的基因诊断和治疗。
