Idiopathic Male Infertility Is Strongly Associated with Aberrant Promoter Methylation of Methylenetetrahydrofolate Reductase (MTHFR)

Abstract

BackgroundAbnormal germline DNA methylation in males has been proposed as a possible mechanism compromising spermatogenesis of some men currently diagnosed with idiopathic infertility. Previous studies have been focused on imprinted genes with DNA methylation in poor quality human sperms. However, recent but limited data have revealed that sperm methylation abnormalities may involve large numbers of genes or shown that genes that are not imprinted are also affected.Methodology/Principal FindingsUsing the methylation-specific polymerase chain reaction and bisulfite sequencing method, we examined methylation patterns of the promoter of methylenetetrahydrofolate reductase (MTHFR) gene (NG_013351: 1538–1719) in sperm DNA obtained from 94 idiopathic infertile men and 54 normal fertile controls. Subjects with idiopathic infertility were further divided into groups of normozoospermia and oligozoospermia. Overall, 45% (41/94) of idiopathic infertile males had MTHFR hypermethylation (both hemimethylation and full methylation), compared with 15% of fertile controls (P<0.05). Subjects with higher methylation level of MTHFR were more likely to have idiopathic male infertility (P-value for trend = 0.0007). Comparing the two groups of idiopathic infertile subjects with different sperm concentrations, a higher methylation pattern was found in the group with oligozoospermia.ConclusionsHypermethylation of the promoter of MTHFR gene in sperms is associated with idiopathic male infertility. The functional relevance of hypermathylation of MTHFR to male fertility warrants further investigation.

The role of epigenetics in idiopathic male infertility

“…Khazamipour and colleagues were the pioneering group who investigated the methylation profiles of MTHFR gene in NOA infertile patients and reported a significant association between methylation status MTHFR gene and infertility in azoospermic males [54]. Recently, DNA methylation aberrations of MTHFR gene promoter in paternal spermatozoa were described in small cohorts of oligozoospermic men and in patients with poor sperm morphology and recurrent spontaneous aberrations [49,55,61] (Table 1). However, in our study, we did not observe a significant association between methylation profiles of MTHFR gene, neither in patients with NOA nor in patients with oligozoospermia, in a Turkish population (Kulaç et al, unpublished data).…”

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

“…In another study by Khazamipour et al, [153], 53 % of men with nonobstructive azoospermia revealed hypermethylation of the MTHFR promoter, while none of the men with obstructive azoospermia exhibited hypermethylation of this gene promoter, suggesting that MTHFR hypermethylation is a specific epigenetic aberration that may specifically contribute to certain types of male infertility. In addition, Wu et al, [154] in a study reported that hypermethylation of MTHFR gene promoter in sperm was associated with idiopathic male infertility. Abnormal DNA methylation of H19 and MEST imprinted genes has also been shown to be associated with oligozoospermia [140], suggesting that spermatogenesis may be particularly vulnerable to changes in the methyl pool brought about by deficiency in MTHFR enzyme.…”

MTHFR promoter hypermethylation may lead to congenital heart defects in Down syndrome

“…Figure 2 shows the pictorial representation of CpG island frequencies in all three study groups. CpG island methylation frequencies has been associated with maternal risk for DS progeny (21,22,23). Several congenital complications are reported in an individual with DS.…”