Mitochondrial DNA sequencing and large-scale genotyping identifies MT-ND4 gene mutation m.11696G>A associated with idiopathic oligoasthenospermia

Abstract

Genetic variants of mitochondrial DNA (mtDNA) were implicated to be associated with male infertility. Our previous whole mitochondrial genome sequencing and association study has identified two susceptibility mtDNA variants for oligoasthenospermia in Han Chinese men. In this study, we tested promising associations in an extended validation using 670 idiopathic oligoasthenospermia cases and 793 healthy controls to identify additional risk variants. We found that the genetic variant of m.11696G>A showed significantly higher frequency in the case group than that in the control group (odds ratio (OR) 2.21, 95% CI 1.21-4.04) (P=7.90×10−3). To elucidate the exact role of the genetic variants in spermatogenesis, two main sperm parameters (sperm count and motility) were taken into account. We found that m.11696G>A was associated with low sperm motility, with the OR of 2.38 (95 % CI 1.27-4.46) (P =5.22×10−3). These results advance our understanding of the genetic susceptibility to oligoasthenospermia and more functional studies are needed to provide insights into its pathogenic mechanism.

Forensic Relationship between ATP6 Gene and Sperm Motility in a Saudi Population

“…This disease was diagnosed by a novel substitution at the position 8684C>T. Wu et al (2019) revealed that sperm mtDNA copy number showed more diagnostic power than mtDNA deletions for the sperm abnormality. Ji et al (2017) revealed that the variant 11696G>A exhibited significant higher frequency in idiopathic oligoasthenospermic Chinese men and this SNP was correlated with low sperm motility supporting the genetic susceptibility to oligoasthenospermia. Holyoake et al (1999) found a polymorphic T to C transition in the ATP6 gene and suggested that the failure of immature spermatids having this mutation to fully develop.…”

“…In spite of this approved identification, published evidence for classifying the samples into normospermic, teratospermic, oligospermic and asthenospermic as listed in WHO (2010) criteria was presented herein. Ji et al (2017) and Liu et al (2017) identified the different infertility cases according to sperm count and motility. Asthenospermia was identified by reduction in sperm motility lower than 40% motile sperms.…”

Potential of Mitochondrial Genome Editing for Human Fertility Health

“…Moreover, Lu et al (2015) showed in a largescale study that two-specific SNPs already associated with mitochondrial pathologies, m.16179C>T and m.12361A>G, were related to alterations in sperm count and/or sperm motility (Lu et al, 2015). The same team also demonstrated in 2017 that the m.11696G>A mutation was associated with a significantly higher risk of asthenospermia (Lu et al, 2015;Ji et al, 2017).…”

Green tea extract increases the quality and reduced DNA mutation of post-thawed Kacang buck sperm

“…Mutation of mtDNA is correlated to reproductive capacity [ 22 ]. The mtDNA genetic variants in the NADH dehydrogenase 1 (ND1) genes may cause decreasing activities of mitochondrial respiratory chain complexes [ 25 ]. Best to our knowledge, there has not yet revealed mtDNA mutation on post-thawed Kacang buck sperm, even in other livestock animals.…”