Abstract
Genetic causes of male infertility that is associated with aging are largely unknown. This study was designed to identify novel pathogenic variants of FOXP3 gene causing azoospermia. One homozygous (c.155 G > T) pathogenic variant of FOXP3 was identified in nine non-obstructive azoospermia patients, and one heterozygous (c.691 C > A) of FOXP3 was found in one non-obstructive azoospermia patient. Pedigrees studies indicated that the homozygous (c.155 G > T) FOXP3 pathogenic variant was inherited, while heterozygous (c.691 C > A) FOXP3 pathogenic variant was acquired. Human testis carrying pathogenic variant exhibited abnormal spermatogenesis. FOXP3 protein was expressed at a lower level or undetected in spermatocytes of mutant testis of non-obstructive azoospermia patients compared to obstructive azoospermia patients. FOXP3 stimulated the proliferation and inhibited the apoptosis of human spermatogonial stem cells, and we further analyzed the targets of FOXP3. We have identified two new pathogenic variants of FOXP3 in non-obstructive azoospermia patients with high incidence, and FOXP3 silencing inhibits the proliferation and enhances the apoptosis of human spermatogonial stem cells. This study provides new insights into the etiology of azoospermia and offers novel pathogenic variants for gene targeting of male infertility.
Highlights
Infertility, a serious health problem associated with aging, affects 10%–15% couples around the world, and male factors account for 50% of the cases [1]
To explore the functional importance of forkhead box protein P3 (FOXP3) in human male infertility, we screened for potential pathogenic www.aging-us.com variants (PV) of FOXP3 in 314 non-obstructive azoospermia (NOA) patients and 14 obstructive azoospermia (OA) controls (Figure 1A)
We identified the same variant in nine NOA patients (Patients 1–9) and another variant in one NOA patient (Patient 10) (Figure 1B and 1C); none of variant was detected in the OA controls (Figure 1B and 1C)
Summary
Infertility, a serious health problem associated with aging, affects 10%–15% couples around the world, and male factors account for 50% of the cases [1]. It has been estimated that there are about 50 million of people with infertility in China. A healthy and mature sperm is essential for male fertility, and notably, gene pathogenic www.aging-us.com variants (PV) and/or defects result in spermatogenesis failure and male infertility. Spermatogenesis, namely the formation and maturation of spermatozoa, involves the self-renewal and differentiation of spermatogonial stem cells (SSCs), meiosis of spermatocytes and spermiogenesis of spermatids in the testis. Human spermatogenesis is an intricate process that is mediated by genetic factors of male germ cells, hormones, and paracrine factors [2]. Conserved orthologs among different species may be required during spermatogenesis with indicative function importance [3]
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