Copy number gain of VCX, X-linked multi-copy gene, leads to cell proliferation and apoptosis during spermatogenesis.

Juan Ji,Xinru Wang,Dengshun Miao,Xiufeng Ling,Hongbing Shen,Chuncheng Lu,Rong Wang,Yufeng Qin,Zhibin Hu,Ran Zhou,Yankai Xia,Ling Song,Yan Zhang,Zhenyao Huang

doi:10.18632/oncotarget.12397

Abstract

Male factor infertility affects one-sixth of couples worldwide, and non-obstructive azoospermia (NOA) is one of the most severe forms. In recent years there has been increasing evidence to implicate the participation of X chromosome in the process of spermatogenesis. To uncover the roles of X-linked multi-copy genes in spermatogenesis, we performed systematic analysis of X-linked gene copy number variations (CNVs) and Y chromosome haplogrouping in 447 idiopathic NOA patients and 485 healthy controls. Interestingly, the frequency of individuals with abnormal level copy of Variable charge, X-linked (VCX) was significantly different between cases and controls after multiple test correction (p = 5.10 × 10−5). To discriminate the effect of gain/loss copies in these genes, we analyzed the frequency of X-linked multi-copy genes in subjects among subdivided groups. Our results demonstrated that individuals with increased copy numbers of Nuclear RNA export factor 2 (NXF2) (p = 9.21 × 10−8) and VCX (p = 1.97 × 10−4) conferred the risk of NOA. In vitro analysis demonstrated that increasing copy number of VCX could upregulate the gene expression and regulate cell proliferation and apoptosis. Our study establishes a robust association between the VCX CNVs and NOA risk.

Highlights

Male infertility, a common reproductive disorder, is estimated to affect approximately one-sixth of couples worldwide [1]
We found that the frequency of individuals with abnormal copy number of Nuclear RNA export factor 2 (NXF2) (OR, 2.46, 95% confidence intervals (CIs) 1.15−5.25, p = 1.66 × 10−2) and VCX (OR, 2.53, 95% CI 1.60−4.02, p = 5.10 × 10−5) in non-obstructive azoospermia (NOA) group was significantly higher than that in control group, while the frequency of FAM47 (OR, 0.27, 95% CI 0.07−0.95, p = 2.89 × 10−2) was significantly lower in NOA groups (Table 2)
Only the association between VCX and NOA risk retained after Bonferroni correction (Table 2)

Summary

Introduction

A common reproductive disorder, is estimated to affect approximately one-sixth of couples worldwide [1]. A significant proportion of male infertility is accompanied by idiopathic azoospermia, most often presenting as non-obstructive azoospermia (NOA), defined as the absence of sperm in the ejaculate without the obstruction of reproductive tract. Especially the Yq microdeletions, in male infertility are well established so far [2,3,4]. It was thought that mammalian X chromosomes were enriched in spermatogenesis genes expressed before meiosis and deficient after meiosis [5,6,7]. The paucity of post-meiotic genes on the X chromosome has been interpreted as a consequence of Meiotic Sex www.impactjournals.com/oncotarget

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Conclusion