Association of a novel human mtDNA ATPase6 mutation with immature sperm cells

Abstract

This study reports the first clearly defined heteroplasmic mutation in immature human sperm cells. The human sperm mitochondrial genome from residue 8186-9341 was analysed with the aim of identifying point mutations which may be associated with human male infertility. The semen samples analysed were obtained from 88 fertile men, 19 with oligozoospermia, and 12 with severe oligozoospermia. Using single strand conformation polymorphism analysis a heteroplasmic T to C transition was detected in the ATPase6 gene, at nucleotide position 8821, in semen samples from one out of 12 (8%) severely oligozoospermic men, but not in oligozoospermic men or normospermic men. This mutation changed the amino acid serine to proline at residue 99 of the mitochondrial ATPase6 in a region which is highly conserved in other vertebrates including rat, bovine, chicken, salmonids and Xenopus. The mutation was detected in semen samples collected from the same man 9 months apart and in peripheral blood lymphocytes. Single sperm cell analyses did not find this mutation in the mature sperm, but the mutation was detected in 7% of immature spermatids. Our finding suggests that immature spermatids with this mutation fail to develop fully.

Detection of Y chromosome microdeletions and mitochondrial DNA mutations in male infertility patients

“…This mutation changed the amino acid serine to proline at residue 99 of mitochondrial ATPase6. This mutation, therefore, may affect sperm motility (Holyoake et al, 1999). These authors also found a high incidence of nucleotide substitutions in the mitochondrial genome, which were associated with poor semen quality.…”

“…In addition, in some studies, deletions in mtDNA tend to develop a decline in motility and fertility in human sperm (Cummins, 1998;Cummins et al, 1998;Kao et al, 1998;O'Connell et al, 2002a,b). Furthermore, it has been demonstrated that mtDNA base substitutions can greatly influence semen quality (Ruiz-Pesini et al, 2000;Holyoake et al, 1999Holyoake et al, , 2001. Therefore, we investigated the relationship between the mtDNA genes ATPase6, Cytb and ND1 and male infertility.…”

“…Holyoake et al (1999) found that severely oligospermic men with a T8821C point mutation in the ATPase6 gene possess immature spermatids. This mutation changed the amino acid serine to proline at residue 99 of mitochondrial ATPase6.…”

A multi-faceted approach to understanding male infertility: gene mutations, molecular defects and assisted reproductive techniques (ART)

“…Recent reports have shown that mtDNA point mutations or multiple deletions, mtDNA single nucleotide polymorphisms (SNPs) and mtDNA haplogroups can greatly influence sperm quality and are associated with asthenozoospermia or oligoasthenozoospermia [128][129][130][131][132][133][134][135][136][137][138]. Among the mitochondrial deletions observed, the deletion of 4977 bp was the most prevalent and abundant one.…”

“…About 8 mutations in ND1 gene were also observed in their study. Holyoake et al, [134] showed that point mutation in the ATPase6 gene at 9055 was commonly seen associated with poor sperm quality. This substitution involves a G to A transition within the ATPase6 gene, changing an alanine to threonine.…”