Functional polymorphism in H2BFWT-5'UTR is associated with susceptibility to male infertility
Functional polymorphism in H2BFWT-5'UTR is associated with susceptibility to male infertility
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DOI：
10.1111/j.1582-4934.2009.00830.x
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发表时间：
2009-08-01
影响因子：
5.3
通讯作者：
Lee, Suman
中科院分区：
文献类型：
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作者：
Lee, Jinu;Park, Hee Suk;Lee, Suman
H2 B组蛋白家族成员W睾丸特异性（H2 BFWT）基因编码睾丸特异性组蛋白，该组蛋白被整合到精子染色质中。直接测序法检测H2 BFWT基因5'非翻译区（5' UTR）内一个与男性不育相关的单核苷酸多态性（-9C > T）。统计学关联分析显示，该基因多态性与男性不育显著相关（n = 442，P = 0.0157），尤其与非无精子症相关（n = 262，P = 0.018）。此外，该多态性还与精子参数相关，尤其是精子数（n = 164，P = 0.0127）和活力（n = 164，P = 0.0076）。我们研究了5 'UTR的遗传变异如何赋予非无精子症的易感性。His-标签H2 BFWT的蛋白质印迹揭示了在转录水平上不存在变化的情况下，-9T和野生型-9C之间在翻译水平上的差异。报告基因分析表明，这种减少的翻译变化起源于上游开放阅读框架（uORF）产生的-9 C到-9 T的变化。最后，精子中H2 BFWT的体内表达显著依赖于非无精子症患者的-9C > T基因型（P = 0.0061）。因此，这种多态性可能会影响uORF对定量重要的组蛋白的翻译效率。我们的数据暗示H2 BFWT作为男性不育的易感因素，可能与其他遗传和环境因素。
H2B histone family, member W, testis-specific (H2BFWT) gene encodes a testis-specific histone that becomes incorporated into sperm chromatin. A male infertility-associated single nucleotide polymorphism (-9C > T) within the 5' untranslated region (5'UTR) of the H2BFWT gene was identified by direct sequencing. Statistical association studies showed the polymorphism significantly associated with male infertility (n = 442, P = 0.0157), especially in non-azoospermia (n = 262, P = 0.018). Furthermore, this polymorphism is also associated with sperm parameters, especially sperm count (n = 164, P = 0.0127) and vitality (n = 164, P = 0.0076). We investigated how the genetic variant at 5'UTR confers susceptibility to non-azoospermia. Western blotting of His-tag H2BFWT revealed a difference at the translational level between -9T and the wild-type -9C in the absence of change at the transcriptional level. Reporter assays showed that this reducing translational change originated from an upstream open reading frame (uORF) generated by the -9C to -9T change. Finally, in vivo H2BFWT expression in sperm was significantly dependent on the -9C > T genotype from non-azoospermia (P = 0.0061). Therefore, this polymorphism could affect the translational efficiency of a quantitatively important histone protein by the uORF. Our data implicate H2BFWT as a susceptibility factor for male infertility, possibly with other genetic and environmental factors.