TEX14中一种新的复合杂合突变通过破坏细胞间桥的组装而导致人类非阻塞性无精子症。

IF 2.3 3区 医学 Q2 GENETICS & HEREDITY
Guotong Li, Shushu Zhou, Yuqian Li, Sana Atta, Xun Xia, Xuan Sha, Rong Hua, Ping Zhou, Zhaolian Wei, Yunxia Cao, Huan Wu
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引用次数: 0

摘要

在脊椎动物精子发生过程中,细胞间桥(ICBs)在细胞间通讯、细胞协调发育和生殖细胞间细胞质含量平衡中起着至关重要的作用。哺乳动物TEX14在睾丸中特异性表达,是ICBs的关键组成部分。它是正常精子发生所必需的;它的缺乏导致减数分裂前期I粗期期减数分裂停止,导致小鼠模型中男性不育伴非阻塞性无精子症(NOA)。然而,TEX14缺乏对精子发生的具体影响尚不清楚。在这项研究中,我们在NOA患者中发现了一个新的复合杂合突变TEX14 (c.802A>T, p.S268C和c.1021C>T, p.R341*)。功能分析表明,这些突变破坏了TEX14的合成。这导致生精失败,其特征是在粗线期减数分裂停止,以及携带突变的睾丸中ICB组装受损。我们的研究结果提供了强有力的证据,证明致病性双等位基因TEX14突变是人类NOA的复发性遗传病因。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A Novel Compound Heterozygous Mutation in TEX14 Causes Human Non-Obstructive Azoospermia by Disrupting the Assembly of Intercellular Bridges.

Intercellular bridges (ICBs) are critical in intercellular communication, coordinated cellular development, and the equilibration of cytoplasmic contents between germ cells during vertebrate spermatogenesis. Mammalian TEX14 is specifically expressed in the testes and is a pivotal component of ICBs. It is indispensable for proper spermatogenesis; its deficiency causes meiotic arrest at the pachytene stage of meiotic prophase I, resulting in male infertility with non-obstructive azoospermia (NOA) in murine models. However, the specific effects of TEX14 deficiency on spermatogenesis remain poorly understood. In this study, we identified a novel compound heterozygous mutation in TEX14 (c.802A>T, p.S268C and c.1021C>T, p.R341*) in a patient with NOA. Functional analyses demonstrated that these mutations disrupted TEX14 synthesis. This led to spermatogenic failure characterized by meiotic arrest at the pachytene stage and impaired ICB assembly in the testes harboring the mutations. Our findings provide robust evidence that pathogenic biallelic TEX14 mutations are recurrent genetic etiologies of NOA in humans.

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来源期刊
Clinical Genetics
Clinical Genetics 医学-遗传学
CiteScore
6.50
自引率
0.00%
发文量
175
审稿时长
3-8 weeks
期刊介绍: Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice. Topics of particular interest are: • Linking genetic variations to disease • Genome rearrangements and disease • Epigenetics and disease • The translation of genotype to phenotype • Genetics of complex disease • Management/intervention of genetic diseases • Novel therapies for genetic diseases • Developmental biology, as it relates to clinical genetics • Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease
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