Homozygous CCDC146 mutation causes oligoasthenoteratozoospermia in humans and mice.

IF 4 1区 生物学 Q1 ZOOLOGY Zoological Research Pub Date : 2024-09-18 DOI:10.24272/j.issn.2095-8137.2024.019
Jing-Wei Ye, Tanveer Abbas, Jian-Teng Zhou, Jing Chen, Meng-Lei Yang, Xiong-Heng Huang, Huan Zhang, Hui Ma, Ao Ma, Bo Xu, Ghulam Murtaza, Qing-Hua Shi, Bao-Lu Shi
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Abstract

Infertility represents a significant health concern, with sperm quantity and quality being crucial determinants of male fertility. Oligoasthenoteratozoospermia (OAT) is characterized by reduced sperm motility, lower sperm concentration, and morphological abnormalities in sperm heads and flagella. Although variants in several genes have been implicated in OAT, its genetic etiologies and pathogenetic mechanisms remain inadequately understood. In this study, we identified a homozygous nonsense mutation (c.916C>T, p.Arg306*) in the coiled-coil domain containing 146 ( CCDC146) gene in an infertile male patient with OAT. This mutation resulted in the production of a truncated CCDC146 protein (amino acids 1-305), retaining only two out of five coiled-coil domains. To validate the pathogenicity of the CCDC146 mutation, we generated a mouse model ( Ccdc146 mut/mut ) with a similar mutation to that of the patient. Consistently, the Ccdc146 mut/mut mice exhibited infertility, characterized by significantly reduced sperm counts, diminished motility, and multiple defects in sperm heads and flagella. Furthermore, the levels of axonemal proteins, including DNAH17, DNAH1, and SPAG6, were significantly reduced in the sperm of Ccdc146 mut/mut mice. Additionally, both human and mouse CCDC146 interacted with intraflagellar transport protein 20 (IFT20), but this interaction was lost in the mutated versions, leading to the degradation of IFT20. This study identified a novel deleterious homozygous nonsense mutation in CCDC146 that causes male infertility, potentially by disrupting axonemal protein transportation. These findings offer valuable insights for genetic counseling and understanding the mechanisms underlying CCDC146 mutant-associated infertility in human males.

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同基因 CCDC146 突变会导致人类和小鼠出现少精症。
不育是一个重大的健康问题,精子的数量和质量是决定男性生育能力的关键因素。少精子症(OAT)的特点是精子活力下降、精子浓度降低、精子头部和鞭毛形态异常。虽然有几个基因的变异与 OAT 有关,但对其遗传病因和发病机制的了解仍然不足。在这项研究中,我们在一名患有 OAT 的不育男性患者体内发现了含线圈域 146(CCDC146)基因的同卵无义突变(c.916C>T,p.Arg306*)。这一突变导致产生了截短的 CCDC146 蛋白(1-305 氨基酸),仅保留了五个盘绕线圈结构域中的两个。为了验证CCDC146突变的致病性,我们建立了一个与患者突变相似的小鼠模型(Ccdc146 mut/mut)。Ccdc146突变/突变小鼠表现出不育症,其特征是精子数量显著减少、运动能力减弱、精子头部和鞭毛存在多种缺陷。此外,Ccdc146突变/突变小鼠精子中的轴突蛋白(包括DNAH17、DNAH1和SPAG6)水平显著降低。此外,人和小鼠的CCDC146都与鞘内转运蛋白20(IFT20)相互作用,但突变型小鼠的CCDC146失去了这种相互作用,导致IFT20降解。这项研究在CCDC146中发现了一种新的有害同卵无义突变,它可能通过破坏轴突蛋白运输而导致男性不育。这些发现为遗传咨询和了解CCDC146突变相关人类男性不育症的机制提供了宝贵的见解。
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来源期刊
Zoological Research
Zoological Research Medicine-General Medicine
CiteScore
7.60
自引率
10.20%
发文量
1937
审稿时长
8 weeks
期刊介绍: Established in 1980, Zoological Research (ZR) is a bimonthly publication produced by Kunming Institute of Zoology, the Chinese Academy of Sciences, and the China Zoological Society. It publishes peer-reviewed original research article/review/report/note/letter to the editor/editorial in English on Primates and Animal Models, Conservation and Utilization of Animal Resources, and Animal Diversity and Evolution.
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