Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
Research Unit of Respiratory Disease, Central South University, Changsha, Hunan, 410011, China.
J Hum Genet. 2022 Apr;67(4):197-201. doi: 10.1038/s10038-021-00985-z. Epub 2021 Nov 24.
Primary ciliary dyskinesia (PCD) is a heterogeneous disease characterized by the failure of mucociliary clearance. Dynein regulatory complex subunit 1 (DRC1) variants can cause PCD by disrupting the nexin link connecting the outer doublets. In this study, we aimed to investigate the clinical and functional impacts of DRC1 variants on respiratory cilia and sperm.
We identified and validated the DRC1 variant by using whole-exome and Sanger sequencing. High-speed video microscopy analysis (HSVA) was used to measure the nasal ciliary beating frequency and pattern in a patient and a healthy control. Hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM) were applied to analyze the morphological and ultrastructural sperm defects resulting from the DRC1 variant.
NM_145038.5:c.1296 G>A, p.(Trp432*), a novel homozygous DRC1 nonsense variant, was identified in a patient from a consanguineous Chinese family. The patient exhibited bronchiectasis, chronic sinusitis, situs solitus, and male infertility. The markedly reduced nasal nitric oxide production rate (3.0 nL/min) was consistent with PCD diagnosis. HSVA showed reduced bending capacity and higher beating frequency of nasal cilia in the patient compared with those in healthy control. The diagnosis of multiple morphological abnormalities of the sperm flagella (MMAF) was confirmed through sperm HE staining and TEM analysis. Following the intracytoplasmic sperm injection treatment, the patient fathered a healthy daughter.
This report is the first to describe a novel DRC1 variant in a patient with PCD and MMAF, and in vitro fertilization was effective for treating infertility in this male patient. Our findings expand the genetic spectrum of PCD and MMAF, and provide a detailed clinical summary and functional analysis of patients with DRC1 variants.
原发性纤毛运动障碍（PCD）是一种以黏液纤毛清除功能障碍为特征的异质性疾病。动力蛋白调节复合物亚单位 1（DRC1）变异可通过破坏连接外二联体的连接蛋白而导致 PCD。本研究旨在探讨 DRC1 变异对呼吸道纤毛和精子的临床和功能影响。
我们通过全外显子组和 Sanger 测序鉴定并验证了 DRC1 变异。高速视频显微镜分析（HSVA）用于测量患者和健康对照者的鼻纤毛摆动频率和模式。苏木精-伊红（HE）染色和透射电子显微镜（TEM）用于分析 DRC1 变异导致的精子形态和超微结构缺陷。
在一个来自近亲结婚的中国家庭的患者中发现了一种新型纯合 DRC1 无义变异 NM_145038.5:c.1296 G>A，p.(Trp432*)。该患者表现为支气管扩张、慢性鼻窦炎、 situs solitus 和男性不育。明显降低的鼻一氧化氮产生率（3.0 nL/min）与 PCD 诊断一致。HSVA 显示患者的鼻纤毛弯曲能力降低，摆动频率高于健康对照者。通过精子 HE 染色和 TEM 分析确认了精子鞭毛多发形态异常（MMAF）的诊断。经胞质内精子注射治疗后，该患者生育了一名健康女儿。
本报告首次描述了 PCD 和 MMAF 患者中一种新型 DRC1 变异，并证明体外受精对该男性患者的不育症有效。我们的研究结果扩展了 PCD 和 MMAF 的遗传谱，并提供了 DRC1 变异患者的详细临床总结和功能分析。
