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.