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Sequence variations of the EGR4 gene in Korean men with spermatogenesis impairment.

ABSTRACT: Egr4 is expressed in primary and secondary spermatocytes in adult mouse testes and has a crucial role in regulating germ cell maturation. The functional loss of Egr4 blocks spermatogenesis, significantly reducing the number of spermatozoa that are produced. In this study, we examined whether EGR4 variants are present in Korean men with impaired spermatogenesis.A total 170 Korean men with impaired spermatogenesis and 272 normal controls were screened. The coding regions including exon-intron boundaries of EGR4 were sequenced by PCR-direct sequencing method.We identified eight sequence variations in the coding region and 3'-UTR regions of the EGR4 gene. Four were nonsynonymous variants (rs771189047, rs561568849, rs763487015, and rs546250227), three were synonymous variants (rs115948271, rs528939702, and rs7558708), and one variant (rs2229294) was localized in the 3'-UTR. Three nonsynonymous variants [c.65_66InsG (p. Cys23Leufs*37), c.236C?>?T (p. Pro79Leu), c.1294G?>?T (p. Val432Leu)] and one synonymous variant [c.1230G?>?A (p. Thr410)] were not detected in controls. To evaluate the pathogenic effects of nonsynonymous variants, we used seven prediction methods. The c.214C?>?A (p. Arg72Ser) and c.236C?>?T (p. Pro79Leu) variants were predicted as "damaging" by SIFT and SNAP2. The c.65_66insG (p. Cys23Leufs*37) variants were predicted as "disease causing" by Mutation Taster, SNPs &GO and SNAP2. The c.867C?>?G (p. Leu289) variants were predicted as "disease causing" only by Mutation Taster.To date, this study is the first to screen the EGR4 gene in relation to male infertility. However, our findings did not clearly explain how nonsynonymous EGR4 variations affect spermatogenesis. Therefore, further studies are required to validate the functional impact of EGR4 variations on spermatogenesis.

SUBMITTER: Sung SR

PROVIDER: S-EPMC5414287 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Sequence variations of the EGR4 gene in Korean men with spermatogenesis impairment.

Sung Se Ra SR Song Seung Hun SH Kang Kyung Min KM Park Ji Eun JE Nam Yeo Jung YJ Shin Yun-Jeong YJ Cha Dong Hyun DH Seo Ju Tae JT Yoon Tae Ki TK Shim Sung Han SH

BMC medical genetics 20170502 1

<h4>Background</h4>Egr4 is expressed in primary and secondary spermatocytes in adult mouse testes and has a crucial role in regulating germ cell maturation. The functional loss of Egr4 blocks spermatogenesis, significantly reducing the number of spermatozoa that are produced. In this study, we examined whether EGR4 variants are present in Korean men with impaired spermatogenesis.<h4>Methods</h4>A total 170 Korean men with impaired spermatogenesis and 272 normal controls were screened. The coding ...[more]

PMID: 28464846

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Project description:Prior studies have demonstrated that combined treatment of testosterone with a progestin induces a more rapid and greater suppression of spermatogenesis than testosterone treatment alone. We hypothesized that the suppressive effects of the combination of testosterone undecanoate (TU) injections plus oral levonorgestrel (LNG) on spermatogenesis may be mediated through a greater perturbation of testicular gene expression than TU alone. To test this hypothesis, we performed open testicular biopsy on 12 different adult healthy subjects: 1) four healthy men as controls; 2) four men 2 wk after TU treatment; and 3) four men 2 wk after TU + LNG administration. RNA isolated from biopsies was used for DNA microarray using the Affymetrix Human Genome U133 Plus 2.0 oligonucleotide microarrays. Gene expression with >or=2-fold changes (P < 0.05) compared with control was analyzed using the National Institutes of Health Database for Annotation, Visualization, and Integrated Discovery 2008 resource. The TU treatment altered the gene expression in 109 transcripts, whereas TU + LNG altered the gene expression in 207 transcripts compared with control. Both TU and TU + LNG administration suppressed gene expression of insulin-like 3; cytochrome P450, family 17, subfamily A1 in Leydig cells; and inhibin alpha in Sertoli cells; they increased proapoptotic transcripts BCL2-like 14, insulin-like growth factor-binding protein 3; and they decreased X-linked inhibitor of apoptosis protein. In comparison with TU treatment alone, TU + LNG treatment upregulated insulin-like 6 and relaxin 1, and downregulated RNA-binding protein transcripts. We conclude that TU + LNG administration induces more changes in testicular gene expression than TU alone. This exploratory study provided a novel and valuable database to study the mechanisms of action of hormonal regulation of spermatogenesis in men and identified testicular-specific molecules that may serve as potential targets for male contraceptive development.

Dataset Information

Sequence variations of the EGR4 gene in Korean men with spermatogenesis impairment.

Publications

Sequence variations of the EGR4 gene in Korean men with spermatogenesis impairment.

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