A dominant-negative mutation of HSF2 associated with idiopathic azoospermia
A dominant-negative mutation of HSF2 associated with idiopathic azoospermia
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HSF2 显性失活突变与特发性无精症相关
DOI：
10.1007/s00439-012-1234-7
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发表时间：
2013-02-01
期刊：
影响因子：
5.3
通讯作者：
Gui, Yaoting
中科院分区：
文献类型：
--
作者：
Mou, Lisha;Wang, Yadong;Gui, Yaoting
特发性无精子症(IA)是一种原因不明的严重男性不育。编码热休克转录因子2的HSF2基因被认为在精子发生过程中发挥重要作用，因为Hsf2基因敲除的雄性小鼠显示出精子发生缺陷。为了验证HSF2是否与人类IA的发病机制有关，我们对766例IA患者和521名已证实有生育能力的男性进行了HSF2所有外显子的测序。发现了一些患者组特有的编码突变，其中包括3个同义突变和5个错义突变。在错义突变中，我们的功能分析表明，一个杂合突变R502H导致HSF2功能完全丧失，该突变通过显性-负效应抑制野生型(WT)等位基因的正常功能，从而导致突变等位基因的显性外显。这些结果支持HSF2在IA的发病机制中的作用，并进一步暗示该转录因子是一个潜在的治疗靶点。
Idiopathic azoospermia (IA) is a severe form of male infertility due to unknown causes. TheHSF2gene, encoding the heat shock transcription factor 2, had been suggested to play a significant role in the spermatogenesis process since theHsf2-knockout male mice showed spermatogenesis defects. To examine whetherHSF2is involved in the pathogenesis of IA in human, we sequenced all the exons ofHSF2in 766 patients diagnosed with IA and 521 proven fertile men. A number of coding mutations private to the patient group, which include three synonymous mutations and five missense mutations, were identified. Of the missense mutations, our functional assay demonstrated that one heterozygous mutation, R502H, caused a complete loss of HSF2 function and that the mutant suppressed the normal function of the wild-type (WT) allele through a dominant-negative effect, thus leading to the dominant penetrance of the mutant allele. These results support a role for HSF2 in the pathogenesis of IA and further implicate this transcription factor as a potential therapeutic target.