TLE6 mutation causes the earliest known human embryonic lethality.
TLE6 mutation causes the earliest known human embryonic lethality.
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DOI：
10.1186/s13059-015-0792-0
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发表时间：
2015-11-05
期刊：
影响因子：
12.3
通讯作者：
Alkuraya FS
中科院分区：
文献类型：
--
作者：
Alazami AM;Awad SM;Coskun S;Al-Hassan S;Hijazi H;Abdulwahab FM;Poizat C;Alkuraya FS
胚胎致死率是模型生物体中个体基因突变的公认表型表达。然而，识别人类胚胎致死基因具有挑战性，特别是当表型在植入前阶段表现出来时。在利用沙特人口高度近亲的特性对人类隐性作用的胚胎致死基因进行编目的持续努力中，我们发现了两个具有女性限制性不孕表型的家庭。使用自合性作图和全外显子组测序，我们将这种表型映射到 TLE6 的单个突变，TLE6 是一种母体效应基因，编码哺乳动物卵母细胞皮质下母体复合体的成员。与已发表的小鼠 Tle6 突变体表型一致，TLE6 突变纯合女性患者的胚胎无法进行早期卵裂，导致不育。人类突变消除了 TLE6 磷酸化，据报道这一步骤对于 PKA 介导的卵母细胞减数分裂 II 的进展至关重要。此外，TLE6 突变削弱了其与皮质下母体复合体成分的结合。在关于皮质下母体亚临界母体复合体成员的人类缺陷的第一份报告中，我们表明 TLE6 突变具有性别特异性，并导致已知最早的人类胚胎致死表型。本文的在线版本 (doi:10.1186/s13059-015-0792-0) 包含补充材料，可供授权用户使用。
Embryonic lethality is a recognized phenotypic expression of individual gene mutations in model organisms. However, identifying embryonic lethal genes in humans is challenging, especially when the phenotype is manifested at the preimplantation stage. In an ongoing effort to exploit the highly consanguineous nature of the Saudi population to catalog recessively acting embryonic lethal genes in humans, we have identified two families with a female-limited infertility phenotype. Using autozygosity mapping and whole exome sequencing, we map this phenotype to a single mutation in TLE6, a maternal effect gene that encodes a member of the subcortical maternal complex in mammalian oocytes. Consistent with the published phenotype of mouse Tle6 mutants, embryos from female patients who are homozygous for the TLE6 mutation fail to undergo early cleavage, with resulting sterility. The human mutation abrogates TLE6 phosphorylation, a step that is reported to be critical for the PKA-mediated progression of oocyte meiosis II. Furthermore, the TLE6 mutation impairs its binding to components of the subcortical maternal complex. In this first report of a human defect in a member of the subcortical maternal subcritical maternal complex, we show that the TLE6 mutation is gender-specific and leads to the earliest known human embryonic lethality phenotype. The online version of this article (doi:10.1186/s13059-015-0792-0) contains supplementary material, which is available to authorized users.