Laboratory of Cell Biology, Department of Microscopy, ICBAS-School of Medicine and Biomedical Sciences, University of Porto, Rua Jorge Viterbo Ferreira, 228, 4050-313, Porto, Portugal.
UMIB-Unit for Multidisciplinary Research in Biomedicine, ICBAS-UP/ ITR-Laboratory for Integrative and Translational Research in Population Health, University of Porto, Porto, Portugal.
J Assist Reprod Genet. 2023 Apr;40(4):765-778. doi: 10.1007/s10815-023-02755-6. Epub 2023 Mar 1.
We here present a female case with primary ciliary dyskinesia (PCD) and infertility. In this report, we also present the evaluation of the patient family, including her twin sister, also with PCD and infertility.
Confirmation of the PCD clinical diagnosis was performed through assessment of cilia motility, by high-speed video microscopy (HSVM), axoneme ultrastructure, by transmission electron microscopy (TEM), and genetic characterization, by whole-exome sequence (WES). Gene expression studies used qPCR for mRNA expression and immunofluorescence to determine cell protein localization.
We identified a homozygous nonsense variant in the DRC1 gene (NM 145038.5:c.352C>T (p.Gln118Ter)) in the female patient with PCD and infertility that fit the model of autosomal recessive genetic transmission. This variant eventually results in a dyskinetic ciliary beat with a lower frequency and a partial lack of both dynein arms as revealed by TEM analysis. Moreover, this variant implies a decrease in the expression of DRC1 mRNA and protein. Additionally, expression analysis suggested that DRC1 may interact with other DRC elements.
Our findings suggest that the DRC1 null variant leads to PCD associated with infertility, likely caused by defects in axoneme from Fallopian tube cilia. Overall, our outcomes contribute to a better understanding of the genetic factors involved in the pathophysiology of PCD and infertility, and they highlight the interaction of different genes in the patient phenotype, which should be investigated further because it may explain the high heterogeneity observed in PCD patients.
我们在此介绍一例原发性纤毛运动障碍（PCD）伴不孕的女性病例。本报告还介绍了患者的家族评估情况，包括其患有 PCD 和不孕的双胞胎姐妹。
通过高速视频显微镜（HSVM）评估纤毛运动、透射电子显微镜（TEM）评估轴丝超微结构以及全外显子组测序（WES）进行遗传特征鉴定，以确认 PCD 的临床诊断。使用 qPCR 检测 mRNA 表达和免疫荧光法确定细胞蛋白定位进行基因表达研究。
我们在患有 PCD 和不孕的女性患者中发现了 DRC1 基因的纯合无义变异（NM 145038.5:c.352C>T (p.Gln118Ter），符合常染色体隐性遗传模式。该变异最终导致纤毛摆动出现动力障碍，摆动频率降低，并且通过 TEM 分析发现动力蛋白臂部分缺失。此外，该变异导致 DRC1 mRNA 和蛋白表达减少。另外，表达分析表明 DRC1 可能与其他 DRC 元件相互作用。
我们的研究结果表明，DRC1 无义变异导致与不孕相关的 PCD，可能是由于输卵管纤毛轴丝缺陷所致。总之，我们的研究结果有助于更好地理解 PCD 和不孕的病理生理学中的遗传因素，并强调了不同基因在患者表型中的相互作用，这需要进一步研究，因为它可能解释了 PCD 患者中观察到的高度异质性。
