Guo Ting, Lu Chenyang, Yang Danhui, Lei Cheng, Liu Ying, Xu Yingjie, Yang Binyi, Wang Rongchun, Luo Hong
Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, China.
Research Unit of Respiratory Disease, Central South University, Changsha, China.
Front Genet. 2022 Jul 12;13:934920. doi: 10.3389/fgene.2022.934920. eCollection 2022.
Primary ciliary dyskinesia (PCD) is a rare genetic disorder, predominantly autosomal recessive. The dynein axonemal assembly factor 4 () is mainly involved in the preassembly of multisubunit dynein protein, which is fundamental to the proper functioning of cilia and flagella. There are few reports of PCD-related pathogenic variants of , and almost no -related articles focused on sperm phenotype. Moreover, the association between and scoliosis has never been reported, to the best of our knowledge. We recruited two patients with a clinical diagnosis of PCD. One came from a consanguineous and another from a non-consanguineous family. Clinical data, laboratory test results, and imaging data were analyzed. Through whole exome sequencing, immunofluorescence, electron microscopy, high-speed video microscopy analysis, and hematoxylin-eosin (HE) staining, we identified the disease-associated variants and validated the pathogenicity. Proband 1 (P1, F1: II-1), a 19-year-old man, comes from a non-consanguineous family-I, and proband 2 (P2, F2: II-1), a 37-year-old woman, comes from a consanguineous family-II. Both had sinusitis, bronchiectasis, situs inversus, and scoliosis. P1 also had asthenoteratozoospermia, and P2 had an immature uterus. Two homozygous pathogenic variants in (NM_130810.4), c.988C > T, p.(Arg330Trp), and (NM_130810.4), c.733 C > T, p.(Arg245*), were identified through whole exome sequencing. High-speed microscopy analysis showed that most of the cilia were static in P1, with complete static of the respiratory cilia in P2. Immunofluorescence showed that the outer dynein arms (ODA) and inner dynein arms (IDA) were absent in the respiratory cilia of both probands, as well as in the sperm flagellum of P1. Transmission electron microscopy revealed the absence of ODA and IDA of respiratory cilia of P2, and HE staining showed irregular, short, absent, coiled, and bent flagella. Our study identified a novel variant c.733C > T, which expanded the spectrum of variants. Furthermore, we linked to asthenoteratozoospermia and likely scoliosis in patients with PCD. This study will contribute to a better understanding of PCD.
原发性纤毛运动障碍（PCD）是一种罕见的遗传性疾病，主要为常染色体隐性遗传。动力蛋白轴丝组装因子4（）主要参与多亚基动力蛋白的预组装，这对纤毛和鞭毛的正常功能至关重要。关于相关的PCD致病变异报道较少，几乎没有关于精子表型的相关文章。此外，据我们所知，与脊柱侧弯之间的关联从未被报道过。我们招募了两名临床诊断为PCD的患者。一名来自近亲家庭，另一名来自非近亲家庭。对临床数据、实验室检查结果和影像学数据进行了分析。通过全外显子组测序、免疫荧光、电子显微镜、高速视频显微镜分析和苏木精-伊红（HE）染色，我们确定了疾病相关变异并验证了其致病性。先证者1（P1，F1：II-1），一名19岁男性，来自非近亲家庭I；先证者2（P2，F2：II-1），一名37岁女性，来自近亲家庭II。两人均患有鼻窦炎、支气管扩张、内脏反位和脊柱侧弯。P1还患有弱畸精子症，P2子宫发育不成熟。通过全外显子组测序确定了（NM_130810.4）中的两个纯合致病变异，c.988C>T，p.（Arg330Trp），以及（NM_130810.4）中的c.733C>T，p.（Arg245*）。高速显微镜分析显示，P1的大多数纤毛静止不动，P2的呼吸道纤毛完全静止。免疫荧光显示，两名先证者的呼吸道纤毛以及P1的精子鞭毛中均不存在外动力蛋白臂（ODA）和内动力蛋白臂（IDA）。透射电子显微镜显示P2的呼吸道纤毛中不存在ODA和IDA，HE染色显示鞭毛不规则、短小、缺失、卷曲和弯曲。我们的研究发现了一个新的变异c.733C>T，扩大了变异谱。此外，我们将与PCD患者的弱畸精子症以及可能的脊柱侧弯联系起来。这项研究将有助于更好地理解PCD。
