title: A single nucleotide polymorphism within the novel sex-linked testis-specific retrotransposed PGAM4 gene influences human male fertility.
abstract: BACKGROUND
  The 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Department of Urology, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Okuda
authors.forename: Akira
authors.initials: A
authors.lastname: Tsujimura
authors.forename: Shinji
authors.initials: S
authors.lastname: Irie
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Fukuhara
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsuoka
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Takao
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Miyagawa
authors.forename: Norio
authors.initials: N
authors.lastname: Nonomura
authors.forename: Morimasa
authors.initials: M
authors.lastname: Wada
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000177:Acrosome / Q000201:enzymology; D005260:Female; D005298:Fertility / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D050172:Genes, X-Linked; D040181:Genetic Diseases, X-Linked / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007248:Infertility, Male / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008540:Meiosis / Q000235:genetics; D009928:Organ Specificity; D010736:Phosphoglycerate Mutase / Q000096:biosynthesis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D013082:Sperm Tail / Q000201:enzymology; D013087:Spermatids / Q000201:enzymology; D013737:Testis / Q000201:enzymology; D049951:X Chromosome Inactivation / Q000235:genetics
chemical_list: D010736:Phosphoglycerate Mutase