Three Novel Mutations in TUBB8 Cause Female Infertility Due to Multiple Morphological Abnormalities of the Oocyte and Early Embryo.

IF 2.6 3区 医学 Q2 OBSTETRICS & GYNECOLOGY
Duan Li, Guanghui Yuan, Xiaoxiao Wang, Jiao Zhuang, Lie Wang, Yingxue Liu, Xiaowen Liu, Linfang Han, Huaiqian Dou, Bing Li, Cuifang Hao
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Abstract

Recent years have seen a global increase in infertility, affecting up to 17.5% of the population. For successful human reproduction, the proper development process of the oocyte, fertilization, and early embryo is required. Assisted reproductive technology (ART), which is the primary treatment for infertility, uses the morphology of oocytes and zygotes as parameters to predict ART outcomes. However, factors such as large perivitelline space (PVS), centrally located granular cytoplasm (CLGC), multi-pronuclei (MPN) formation, and final early embryonic development arrest often lead to repeated failure of ART treatment. Genetic analysis has identified various pathogenic genetic factors contributing to infertility, suggesting that genetic variation plays a significant role in recurrent ART treatment failure. However, maternal genes responsible for large PVS, CLGC, and MPN formation are rarely reported. In this study involving Whole Exome Sequencing (WES) and Sanger sequencing validation, three novel heterozygous missense mutations (p.M403V, p.R306H, p.H190Y) in TUBB8 were identified as being associated with large PVS, CLGC, MPN formation, and early embryonic development arrest. These mutant sites are evolutionarily conserved in different species. Additionally, in silico and in vitro experiments demonstrate that these variants disrupt the conformation, expression, and microtubule structures of the TUBB8 protein. Therefore, these findings contribute significantly to understanding TUBB8-related large PVS, CLGC, and MPN formation in the context of ARTs. This broadens our insight into the genetic connection in human reproduction and emphasizes the importance of comprehensive genetic screening and personalized intervention strategies for PVS, CLGC, and MPN formation.

由于卵母细胞和早期胚胎的多种形态异常,TUBB8的三个新突变导致女性不育。
近年来,不孕不育在全球范围内有所增加,影响到17.5%的人口。为了人类的成功繁殖,需要卵母细胞、受精和早期胚胎的正常发育过程。辅助生殖技术(ART)是不孕症的主要治疗方法,它使用卵母细胞和受精卵的形态作为预测ART结果的参数。然而,诸如卵泡周间隙大(PVS)、位于中心的颗粒细胞质(CLGC)、多原核(MPN)形成以及最终的早期胚胎发育停滞等因素往往导致ART治疗的反复失败。遗传分析已经确定了导致不孕症的各种致病遗传因素,表明遗传变异在复发性ART治疗失败中起着重要作用。然而,母体基因负责大PVS, CLGC和MPN的形成很少被报道。在这项涉及全外显子组测序(WES)和Sanger测序验证的研究中,发现TUBB8中三个新的杂合错感突变(p.M403V, p.R306H, p.H190Y)与大PVS、CLGC、MPN形成和早期胚胎发育停滞有关。这些突变位点在不同的物种中是进化保守的。此外,计算机和体外实验表明,这些变异破坏了TUBB8蛋白的构象、表达和微管结构。因此,这些发现有助于理解tubb8相关的大pv、CLGC和MPN在art背景下的形成。这拓宽了我们对人类生殖中遗传联系的认识,并强调了对PVS、CLGC和MPN形成进行全面遗传筛查和个性化干预策略的重要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Reproductive Sciences
Reproductive Sciences 医学-妇产科学
CiteScore
5.50
自引率
3.40%
发文量
322
审稿时长
4-8 weeks
期刊介绍: Reproductive Sciences (RS) is a peer-reviewed, monthly journal publishing original research and reviews in obstetrics and gynecology. RS is multi-disciplinary and includes research in basic reproductive biology and medicine, maternal-fetal medicine, obstetrics, gynecology, reproductive endocrinology, urogynecology, fertility/infertility, embryology, gynecologic/reproductive oncology, developmental biology, stem cell research, molecular/cellular biology and other related fields.
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