Mutations in PADI6 Cause Female Infertility Characterized by Early Embryonic Arrest
Mutations in PADI6 Cause Female Infertility Characterized by Early Embryonic Arrest
复制标题
PADI6 突变导致女性不孕，表现为早期胚胎停滞
DOI：
10.1016/j.ajhg.2016.06.024
复制
发表时间：
2016-09-01
影响因子：
9.8
通讯作者：
Wang, Lei
中科院分区：
文献类型：
--
作者：
Xu, Yao;Shi, Yingli;Wang, Lei
早期胚胎停滞是女性不孕的主要原因之一。然而，由于表型评估的困难，人类早期胚胎停滞的遗传决定因素在很大程度上是未知的。随着辅助生殖技术的发展，现在可以仔细评估早期人类胚胎停滞的表型。在这里，我们描述了一个具有隐性遗传模式的女性不育症的近亲家庭，其特征是在体外受精（IVF）和卵胞浆内单精子注射（ICSI）周期中反复出现早期胚胎停滞。我们已经确定了一个纯合的PADI 6无义突变（c.1141C>T [p.G1n381*]），这是负责表型。在一组36名胚胎显示发育停滞的个体中进行的PADI 6突变分析确定了两名受影响的个体具有复合杂合突变（c.2009_2010del [p.G1u670Glyfs*48]和c.633T>A [p.His211G1n]; c.1618G>A [p.Gly540Arg]和c.970C>T [p.G1n3241）。免疫染色显示受影响个体的卵母细胞中缺乏PADI 6。此外，在受影响个体的胚胎中，磷酸化RNA聚合酶II的量和参与合子基因组激活的七个基因的表达水平降低。该表型与Padi 6敲除小鼠一致。这些发现加深了我们对人类早期胚胎停滞的遗传基础的理解，这在很大程度上被忽视了孟德尔表型。我们的发现为揭示早期胚胎停滞导致不孕的其他遗传原因奠定了基础。
Early embryonic arrest is one of the major causes of female infertility. However, because of difficulties in phenotypic evaluation, genetic determinants of human early embryonic arrest are largely unknown. With the development of assisted reproductive technology, the phenotype of early human embryonic arrest can now be carefully evaluated. Here, we describe a consanguineous family with a recessive inheritance pattern of female infertility characterized by recurrent early embryonic arrest in cycles of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). We have identified a homozygous PADI6 nonsense mutation (c.1141C>T [p.G1n381*]) that is responsible for the phenotype. Mutational analysis of PADI6 in a cohort of 36 individuals whose embryos displayed developmental arrest identified two affected individuals with compound-heterozygous mutations (c.2009_2010del [p.G1u670Glyfs*48] and c.633T>A [p.His211G1n]; c.1618G>A [p.Gly540Arg] and c.970C>T [p.G1n3241). Immunostaining indicated a lack of PADI6 in affected individuals' oocytes. In addition, the amount of phosphorylated RNA polymerase II and expression levels of seven genes involved in zygotic genome activation were reduced in the affected individuals' embryos. This phenotype is consistent with Padi6 knockout mice. These findings deepen our understanding of the genetic basis of human early embryonic arrest, which has been a largely ignored Mendelian phenotype. Our findings lay the foundation for uncovering other genetic causes of infertility resulting from early embryonic arrest.