Abstract
BackgroundThe development of novel fertilization treatments, including in vitro fertilization and intracytoplasmic injection, has made pregnancy possible regardless of the level of activity of the spermatozoa; however, the etiology of male-factor infertility is poorly understood. Multiple studies, primarily through the use of transgenic animals, have contributed to a list of candidate genes that may affect male infertility in humans. We examined single nucleotide polymorphisms (SNPs) as a cause of male infertility in an analysis of spermatogenesis-specific genes.Methods and FindingWe carried out the prevalence of SNPs in the coding region of phosphoglycerate mutase 4 (PGAM4) on the X chromosome by the direct sequencing of PCR-amplified DNA from male patients. Using RT-PCR and western blot analyses, we identified that PGAM4 is a functional retrogene that is expressed predominantly in the testes and is associated with male infertility. PGAM4 is expressed in post-meiotic stages, including spermatids and spermatozoa in the testes, and the principal piece of the flagellum and acrosome in ejaculated spermatozoa. A case-control study revealed that 4.5% of infertile patients carry the G75C polymorphism, which causes an amino acid substitution in the encoded protein. Furthermore, an assay for enzymatic activity demonstrated that this polymorphism decreases the enzyme’s activity both in vitro and in vivo.ConclusionThese results suggest that PGAM4, an X-linked retrogene, is a fundamental gene in human male reproduction and may escape meiotic sex chromosome inactivation. These findings provide fresh insight into elucidating the mechanisms of male infertility.
Highlights
These results suggest that phosphoglycerate mutase 4 (PGAM4), an X-linked retrogene, is a fundamental gene in human male reproduction and may escape meiotic sex chromosome inactivation
A single nucleotide polymorphism (SNP) causing an amino acid substitution was common in infertile human men and was shown to reduce the enzyme’s activity. These results indicate that PGAM4, located on the X chromosome, is a functional retrogene that is associated with male infertility
Gene Expression of PGAM1 and PGAM4 To determine whether PGAM4 mRNA is present in the testes, we performed RT–PCR amplification using total RNA from human testes (Fig. 1A) and conventional PCR on samples from a testis-specific cDNA library (Fig. S2A)
Summary
At least 40% of cases of human infertility have no obvious underlying cause, male factors account for approximately 30–40% [1]. It is important both to search for genes that are associated with infertility and to identify genetic risk factors for male infertility Retrotransposition can create both pseudogenes and functional retrogenes by integration of parental mRNA into the genome by reverse transcriptase. The mouse genes encoding the spermatogenic cell-specific glycolytic enzyme phosphoglycerate kinase (PGK) 2 (Pgk2) –which is conserved in humans–[7,8] and aldolase 1 A retrogenes 1 and 2 (Aldoart and Aldoart2) [9] were created by retrotransposition These genes are expressed at meiotic or postmeiotic stages and play an essential role in both sperm motility and male infertility in mice. We examined single nucleotide polymorphisms (SNPs) as a cause of male infertility in an analysis of spermatogenesis-specific genes
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