Abstract
Male infertility has become a serious health and social problem troubling approximately 15% of couples worldwide; however, the genetic and phenotypic heterogeneity of human infertility poses a substantial obstacle to effective diagnosis and therapy. A previous study reported that heterozygous mutations in solute carrier family 26 member 8(SLC26A8 , NG_033897.1) were causatively linked to asthenozoospermia. Interestingly, in our research, three deleterious heterozygous mutations ofSLC26A8 were separately detected in three unrelated patients who were suffered from teratozoospermia. These three heterozygous mutations resulted in the reduce of SLC26A8 expression in transfected cells, while no disrupt expression of SLC26A8 was observed in sperm from the affected individuals. Noticeably, two of the three SLC26A8 heterozygous mutations detected in the patients were inherited from their fertile fathers. Thus, we suggested that male infertility associated withSLC26A8 mutations should be involved in a recessive-inherited pattern, considering the infertile homozygous Slc26a8 KO male mice. Given that SLC26A8 heterozygous mutations were detected in the infertile patients, and SLC26A8 is predominantly expressed in the various germ cells during spermatogenesis, the heterozygous mutations inSLC26A8 may not be the direct genetic cause but contribute to male infertility to a certain degree.
KER WORDS: SLC26A8 , heterozygous mutation, recessive inheritance, male infertility, WES
INTRODUCTION
World Health Organization (WHO) has deemed that infertility is a global health problem that affects about 15% of couples in the world, and male infertility accounts for about 30%~50% (Jiao et al., 2021). Spermatogenesis is regulated by multiple gene expression strictly, and gene variations disrupting protein function often lead to defective sperm development (Noveski et al., 2016). Therefore, male infertility has a strong genetic basis. In spite of some disease-related genes that have been investigated, each gene is possibly responsible for only a small fraction of pathogenic factors. Due to the high genetic heterogeneity in male infertility (Kasak et al., 2021), the pathogenesis and mechanisms of male infertility have not been comprehensively studied.
We have noticed that Dirami T et al . reported that three heterozygous missense mutations(c.260G>A [p.Arg87Gln], c.2434G>A [p.Glu812Lys] and c.2860C>T [p.Arg954Cys]) in solute carrier family 26 member 8(SLC26A8 , NG_033897.1) could result in male infertility associated with asthenozoospermia (Dirami et al., 2013). The authors further demonstrated heterozygous mutations in SLC26A8 might impair the formation of SLC26A8-CFTR complex, thus disrupting the capacity to activate CFTR-dependent anion transport (Dirami et al., 2013). These events finally damaged the CFTR-dependent sperm-activation in sterile patients (Dirami et al., 2013). However, Slc26a8-/- mice presented infertile phenotype butSlc26a8 +/- mice showed normal fertility (Touréet et al., 2007; Rode et al., 2012), indicated Slc26a8 is involved in reproduction through recessive-inheritance manner. The disparate inherited pattern between humans and mice makes us confused. Does SLC26A8 play diverse roles in the reproductive process of humans and mice? More importantly, what kind of genetic model isSLC26A8 participating in spermatogenesis? Therefore, a more comprehensive interrogation of the function of SLC26A8 in male infertility is needed to further boost clinical diagnosis.
Interestingly, it was a remarkable fact that we found three heterozygous mutations of SLC26A8 respectively in three unrelated infertile males with teratozoospermia in this study, and the aberrant sperm morphology and ultrastructure were confirmed by electron microscope. Surprisingly, two of these heterozygous mutations of SLC26A8detected in the patients were inherited from their fathers who have no reproductive barriers. The deleterious effect of the three heterozygous mutations on SLC26A8 expression was confirmed by western blotting in vitro. However, no significant expression difference of SLC26A8 was exhibited in sperm between patients and normal control. Therefore, we suggested that the heterozygous mutations in SLC26A8 might not be the immediate cause of asthenozoospermia but participate in spermiogenesis to a certain extent.