The potential impact of tumor suppressor genes on human gametogenesis: a case-control study

Abstract

Purpose To study the incidence of tumor suppressor gene (TSG) mutations in men and women with impaired gametogenesis. Methods Gene association analyses were performed on blood samples in two distinct patient populations: males with idiopathic male infertility and females with unexplained diminished ovarian reserve (DOR). The male study group consisted of men with idiopathic azoospermia, oligozoospermia, asthenozoospermia, or teratozoospermia. Age-matched controls were men with normal semen analyses. The female study group consisted of women with unexplained DOR with anti-Müllerian hormone levels ≤ 1.1 ng/mL. Controls were age-matched women with normal ovarian reserve (> 1.1 ng/mL). Results Fifty-seven male cases (mean age = 38.4; mean sperm count = 15.7 ± 12.1; mean motility = 38.2 ± 24.7) and 37 agematched controls (mean age = 38.0; mean sperm count = 89.6 ± 37.5; mean motility = 56.2 ± 14.3) were compared. Variants observed in CHD5 were found to be enriched in the study group (p = 0.000107). The incidence of CHD5 mutation c.*3198_*3199insT in the 3′UTR (rs538186680) was significantly higher in cases compared to controls (p = 0.0255). 72 DOR cases (mean age = 38.7; mean AMH = 0.5 ± 0.3; mean FSH = 11.7 ± 12.5) and 48 age-matched controls (mean age = 37.6; mean AMH = 4.1 ± 3.0; mean FSH = 7.1 ± 2.2) were compared. Mutations in CHD5 (c.-140A>C), RB1 (c.1422-18delT, rs70651121), and TP53 (c.376-161A>G, rs75821853) were found at significantly higher frequencies in DOR cases compared to controls (p ≤ 0.05). In addition, 363 variants detected in the DOR patients were not present in the control group. Conclusion Unexplained impaired gametogenesis in both males and females may be associated with genetic variation in TSGs. TSGs, which play cardinal roles in cell-cycle control, might also be critical for normal spermatogenesis and oogenesis. If validated in larger prospective studies, it is possible that TSGs provide an etiological basis for some patients with impaired gametogenesis.

The possible impact of DNA‐binding chromodomain‐helicase 5 polymorphisms on male infertility: A case–control study

“…In one study, rs1883603, rs9434741, and rs17436816 polymorphisms of the CHD5 gene in endometriosis were examined, and it was found that rs9434741 was significantly associated with endometriosis 21 . Hershlag et al showed that the CHD5 c.*3198_*3199T, 3′‐UTR (rs538186680) mutation was significantly higher in infertile male specimens than in controls, so idiopathic causes of infertility may be associated with CHD5 disorders 22 . Much research has been done on various polymorphisms of the CHD5 gene, but so far, no study has been reported on the association of this gene with male infertility.…”

“…21 Hershlag et al showed that the CHD5 c.*3198_*3199T, 3 0 -UTR (rs538186680) mutation was significantly higher in infertile male specimens than in controls, so idiopathic causes of infertility may be associated with CHD5 disorders. 22 Much research has been done on various polymorphisms of the CHD5 gene, but so far, no study has been reported on the association of this gene with male infertility. The rs7513548 was significantly associated with diffuse melanoma.…”

“…Also, rs9434741 of the CHD5 gene was significantly associated with endometriosis in women 21 . The Hershlag study showed that the CHD5 rs538186680 was significantly higher in infertile males than in controls, so idiopathic causes of infertility may be associated with CHD5 disorders 22 …”

“…21 The Hershlag study showed that the CHD5 rs538186680 was significantly higher in infertile males than in controls, so idiopathic causes of infertility may be associated with CHD5 disorders. 22 Given the high prevalence of infertility across the world and in Iran, where half of the cases are related to men, and considering the significance and function of childbearing in upholding the family, it is an excellent way to determine the mechanism of infertility as well as a treatment strategy and diagnosis before puberty.…”

Analysis of partial Y chromosome microdeletions and NGS data in Lithuanian infertile men

“…A variant of TP63 oncogene of uncertain clinical signi cance was identi ed in an individual with azoospermia clinic. Variants of the TP63 gene have been found to be associated with male infertility, including azoospermia, oligospermia, teratospermia, or asthenospermia (Hershlag et al 2019).…”