Cavarocchi Emma, Drouault Maëva, Ribeiro Joao C, Simon Violaine, Whitfield Marjorie, Touré Aminata
Institute for Advanced Biosciences, INSERM U 1209, CNRS UMR 5309, Université Grenoble Alpes, Team "Physiopathology and Pathophysiology of Sperm Cells", Grenoble, France.
Faculty of Medicine, Centre Hospitalier Universitaire de Québec-Research Center, Department of Obstetrics, Gynecology, and Reproduction, Université Laval, Quebec, Canada.
Andrology. 2025 Jul;13(5):1044-1064. doi: 10.1111/andr.13828. Epub 2025 Jan 2.
In mammals, sperm fertilization potential relies on efficient progression within the female genital tract to reach and fertilize the oocyte. This fundamental property is supported by the flagellum, an evolutionarily conserved organelle, which contains dynein motor proteins that provide the mechanical force for sperm propulsion and motility. Primary motility of the sperm cells is acquired during their transit through the epididymis and hyperactivated motility is acquired throughout the journey in the female genital tract by a process called capacitation. These activation processes rely on the micro-environment of the genital tracts. In particular, during capacitation, a panoply of ion transporters located at the surface of the sperm cells mediate complex ion exchanges, which induce an increase in plasma membrane fluidity, the alkalinization of the cytoplasm and protein phosphorylation cascades that are compulsory for sperm hyperactivation and fertilization potential. As a consequence, both structural and functional defects of the sperm flagellum can affect sperm motility, resulting in asthenozoospermia, which constitutes the most predominant pathological condition associated with human male infertility.
Herein, we have performed a literature review to provide a comprehensive description of the recent advances in the genetics of human asthenozoospermia.
We describe the currently knowledge on gene mutations that affect sperm morphology and motility, namely, asthenoteratozoospermia; we also specify the gene mutations that exclusively affect sperm function and activation, resulting in functional asthenozoospermia. We discuss the benefit of this knowledge for patient and couple management, in terms of genetic counselling and diagnosis of male infertility as a sole phenotype or in association with ciliary defects. Last, we discuss the current strategies that have been initiated for the development of potential therapeutical and contraceptive strategies targeting genes that are essential for sperm function and activation.
在哺乳动物中，精子的受精潜力依赖于其在雌性生殖道内的高效推进，以到达并使卵母细胞受精。这一基本特性由鞭毛支撑，鞭毛是一种进化上保守的细胞器，其中含有动力蛋白，为精子的推进和运动提供机械力。精子细胞的初级运动能力在其通过附睾的过程中获得，而超活化运动能力则在雌性生殖道的整个行程中通过一个称为获能的过程获得。这些激活过程依赖于生殖道的微环境。特别是在获能过程中，位于精子细胞表面的一系列离子转运蛋白介导复杂的离子交换，这会导致质膜流动性增加、细胞质碱化以及蛋白质磷酸化级联反应，这些对于精子的超活化和受精潜力都是必不可少的。因此，精子鞭毛的结构和功能缺陷都会影响精子的运动能力，导致弱精子症，这是与人类男性不育相关的最主要病理状况。
在此，我们进行了一项文献综述，以全面描述人类弱精子症遗传学的最新进展。
我们描述了目前关于影响精子形态和运动能力的基因突变的知识，即弱畸精子症；我们还明确了仅影响精子功能和激活的基因突变，从而导致功能性弱精子症。我们从遗传咨询以及将男性不育作为单一表型或与纤毛缺陷相关的诊断方面，讨论了这些知识对患者和夫妇管理的益处。最后，我们讨论了目前已启动的针对精子功能和激活所必需基因开发潜在治疗和避孕策略的策略。
