Rare double sex and mab-3-related transcription factor 1 regulatory variants in severe spermatogenic failure.
Rare double sex and mab-3-related transcription factor 1 regulatory variants in severe spermatogenic failure.
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DOI：
10.1111/andr.12063
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发表时间：
2015-09
期刊：
影响因子：
4.5
通讯作者：
Lopes AM
中科院分区：
文献类型：
--
作者：
Lima AC;Carvalho F;Gonçalves J;Fernandes S;Marques PI;Sousa M;Barros A;Seixas S;Amorim A;Conrad DF;Lopes AM
DMRT1（双性和 mab-3 相关转录因子 1）基因长期以来一直与脊椎动物的性别决定途径相关，并且已知在小鼠性腺发育和精子发生维持中发挥重要作用。在人类中，含有 DMRT 基因簇的基因组区域与性发育障碍有关，最近 DMRT1 缺失被证明与非梗阻性无精症 (NOA) 相关。在这项工作中，我们采用不同的方法筛选一组葡萄牙 NOA 患者的 DMRT1 外显子插入和缺失（通过 MLPA；n=68）和点突变（通过 Sanger 测序；n=155）。我们发现了三种新的患者特异性非编码杂合性变异，357 个地理匹配的对照中不存在这些变异。其中之一是具有假定调节作用的复杂变体 (c.-223_-219CGAAA>T)，位于参与 Dmrt1 抑制的保守序列内的启动子区域。此外，虽然 DMRT1 结构域在脊椎动物中高度保守，并且在人类群体中表现出多样性水平降低，但与对照组相比，2 种罕见的同义替换（rs376518776 和 rs34946058）和 2 种可能影响 DMRT1 表达和剪接的罕见非编码变异（rs144122237 和 rs200423545）在患者中的比例过高376 只葡萄牙对照组（301 只可育，75 只正常精子）。总体而言，我们之前和目前的结果表明，NOA 中 DMRT1 剂量的变化也可能通过基因失调过程发挥作用，尽管 DMRT1 有害变异似乎很少见。
The DMRT1 (doublesex and mab-3 related transcription factor 1) gene has long been linked to sex-determining pathways across vertebrates and is known to play an essential role in gonadal development and maintenance of spermatogenesis in mice. In humans, the genomic region harboring the DMRT gene cluster has been implicated in disorders of sex development and recently DMRT1 deletions were shown to be associated with non-obstructive azoospermia (NOA). In this work we have employed different methods to screen a cohort of Portuguese NOA patients for DMRT1 exonic insertions and deletions (by MLPA; n=68) and point mutations (by Sanger sequencing; n=155). We have found three novel patient-specific non-coding variants in heterozygosity that were absent from 357 geographically matched controls. One of these is a complex variant with a putative regulatory role (c.-223_-219CGAAA>T), located in the promoter region within a conserved sequence involved in Dmrt1 repression. Moreover, while DMRT1 domains are highly conserved across vertebrates and show reduced levels of diversity in human populations, 2 rare synonymous substitutions (rs376518776 and rs34946058) and 2 rare non-coding variants that potentially affect DMRT1 expression and splicing (rs144122237 and rs200423545) were overrepresented in patients when compared to 376 Portuguese controls (301 fertile and 75 normozoospermic). Overall our previous and present results suggest a role of changes in DMRT1 dosage in NOA potentially also through a process of gene misregulation, even though DMRT1 deleterious variants seem to be rare.