Human asthenozoospermia: Update on genetic causes, patient management, and clinical strategies

Abstract

Background: 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.

Objectives: Herein, we have performed a literature review to provide a comprehensive description of the recent advances in the genetics of human asthenozoospermia.

Results and discussion: 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.

Keywords: asthenozoospermia; contraception; flagellar morphology; gene mutation; signaling; therapeutics.

FIGURE 1

Structure of sperm flagella and motile cilia (9 + 2). (A) Schematic representation of the structure of cellular appendages such as the flagellum (on the left) and motile cilia (on the right), which share the axoneme as a common cytoskeletal backbone. A transversal axonemal section is depicted in the middle and shows the classical 9 + 2 microtubular organisation and the additional protein complexes regulating its bending. In addition, the centriole is show at the base of motile cilia, while spermatozoa display unique periaxonemal structures of the flagellum, namely, the annulus, the outer dense fibers, and the fibrous sheath. (B) Structure of the sperm flagellum of human spermatozoa visualized by transmission electron microscopy (TEM). Upper panel: longitudinal section showing the annulus at the junction of the midpiece (with the mitochondria) and the principal piece (with the fibrous sheath). Lower panel: transversal section through the midpiece showing the mitochondria, the outer dense fibers, and axonemal microtubules.

FIGURE 2

Phenotype and genetics of asthenoteratozoospermia, with a focus on the multiple morphological anomalies of the sperm flagella (MMAF) phenotype. (A) Sperm structural and ultrastructural defects observed in the ejaculate of patients showing the MMAF phenotype, by means of optical microscopy and transmission electron microscopy (TEM), respectively. Spermatozoa mostly display absent, short, coiled, abnormal calibre flagella, as well as impaired mitochondrial sheath and excessive retained cytoplasm. (B) Causal genes, listed by protein function, associated to non‐syndromic asthenoteratozoospermia in humans, namely, the MMAF phenotype—either validated (black) or putative (gray) mutations—or other sperm morphological defects (blue).

FIGURE 3

Physiological relevance of sperm functional activation and genetics of functional asthenozoospermia. (A) As a response to external stimuli within the male and female genital tracts, spermatozoa undergo a series of molecular changes mainly involving ion fluxes and phosphorylation pathways essential for the acquisition of motility and the fertilization potential. (B) Subcellular localization of the causal genes associated to human functional asthenozoospermia.

FIGURE 4

Ciliopathies and male infertility. (A) Phenotypical spectrum listing the frequently observed symptoms for primary cilia dyskinesia (PCD), on the left, and other ciliopathies, such as Bardel‒Biedl syndrome (BBS), Joubert syndrome (JBTS), and nephronophthisis (NPHP), on the right. (B) Causal genes, listed by protein function, for ciliopathy‐associated asthenoteratozoospermia in humans, namely, the PCD‐related multiple morphological abnormalities of flagella (MMAF) phenotype (black), other PCD‐related sperm morphological defects (blue) and MMAF phenotype associated to other ciliopathies (violet).