亲爱的研友该休息了!由于当前在线用户较少,发布求助请尽量完整的填写文献信息,科研通机器人24小时在线,伴您度过漫漫科研夜!身体可是革命的本钱,早点休息,好梦!

Whole-exome sequencing of a cohort of infertile men reveals novel causative genes in teratozoospermia that are chiefly related to sperm head defects

精子 男性不育 生物 外显子组测序 不育 男科 候选基因 遗传学 基因 表型 医学 怀孕
作者
Yaqian Li,Yan Wang,Yuting Wen,Tao Zhang,Xiaodong Wang,Chuan Jiang,Rui Zheng,Fan Zhou,Daijuan Chen,Yihong Yang,Ying Shen
出处
期刊:Human Reproduction [Oxford University Press]
卷期号:37 (1): 152-177 被引量:35
标识
DOI:10.1093/humrep/deab229
摘要

Abstract STUDY QUESTION Can whole-exome sequencing (WES) and in vitro validation studies identify new causative genes associated with teratozoospermia, particularly for sperm head defect? SUMMARY ANSWER We investigated a core group of infertile patients, including 82 cases with unexplained abnormal sperm head and 67 individuals with multiple morphological abnormalities of the sperm flagella (MMAF), and revealed rare and novel deleterious gene variants correlated with morphological abnormalities of the sperm head or tail defects. WHAT IS KNOWN ALREADY Teratozoospermia is one of the most common factors causing male infertility. Owing to high phenotypic variability, currently known genetic causes of teratozoospermia can only explain a rather minor component for patients with anomalous sperm-head shapes, and the agents responsible for atypical sperm head shapes remain largely unknown. STUDY DESIGN, SIZE, DURATION We executed WES analysis of a Chinese cohort of patients (N = 149) with teratozoospermia to identify novel genetic causes particularly for defective sperm head. We also sought to reveal the influence of different abnormalities of sperm morphology on ICSI outcome. PARTICIPANTS/MATERIALS, SETTING, METHODS In this study, a cohort of 149 infertile men (82 with abnormal sperm head and 67 with MMAF) were recruited. We implemented WES on infertile patients and analyzed the negative effects of the mutations of candidate genes on their protein conformations and/or expression. We also investigated the candidate genes’ spatiotemporal expression/localization during spermatogenesis in both humans and mice, and explored their interactions with proteins that are known to be involved in sperm development. We also compared the ICSI outcomes of the affected individuals with various aberrations in sperm morphology. MAIN RESULTS AND THE ROLE OF CHANCE We identified rare and deleterious variants of piwi like RNA-mediated gene silencing 4 (PIWIL4: 1/82 patients, 1.21%), coiled-coil and C2 domain containing 1B (CC2D1B: 1/82 patients, 1.21%), cyclin B3 (CCNB3: 1/82 patients, 1.21%), KIAA1210 (KIAA1210: 2/82 patients, 2.43%) and choline phosphotransferase 1 (CHPT1: 1/82 patients, 1.21%), which are novel correlates of morphological abnormalities of the sperm head; functional evidence supports roles for all of these genes in sperm head formation. The mutations of septin 12 (SEPTIN12: 2/82 patients, 2.43%) are suggested to be associated with acrosome defects. We additionally observed novel causative mutations of dynein axonemal heavy chain 2 (DNAH2: 1/67 patients, 1.49%), dynein axonemal heavy chain 10 (DNAH10: 1/67 patients, 1.49%) and dynein axonemal heavy chain 12 (DNAH12: 1/67 patients, 1.49%) in patients with MMAF, and revealed a significantly lower fertilization rate of the abnormal sperm-head group compared to the MMAF group following ICSI. Consequently, our study also suggests that the mutations of PIWIL4 and CC2D1B might be circumvented by ICSI to a degree, and that CHPT1 and KIAA1210 loss-of-function variants might be associated with failed ICSI treatment. LIMITATIONS, REASONS FOR CAUTION In this study, we discovered the relationship between the genotype and phenotype of the novel causative genes of sperm head deformities in humans. However, the molecular mechanism of the relevant genes involved in sperm head development needs to be further illuminated in future research. Furthermore, evidence should be provided using knockout/knock-in mouse models for additional confirmation of the roles of these novel genes in spermatogenesis. WIDER IMPLICATIONS OF THE FINDINGS This cohort study of 149 Chinese infertile men documents novel genetic factors involved in teratozoospermia, particularly in anomalous sperm head formation. For the first time, we suggest that SEPTIN12 is related to human acrosomal hypoplasia, and that CCNB3 is a novel causative gene for globozoospermia in humans. We also uncovered variants in two genes—KIAA1210 and CHPT1associated with acrosomal biogenesis in patients with small or absent acrosomes. Additionally, it is postulated that loss-of-function mutations of PIWIL4 and CC2D1B have a contribution to the abnormal sperm-head formation. Furthermore, we are first to demonstrate the influence of different sperm morphologies on ICSI outcomes and indicates that the abnormal sperm head may play a significant role in fertilization failure. Our findings therefore provide valuable information for the diagnosis of teratozoospermia, particularly with respect to abnormalities of the sperm head. This will allow clinicians to adopt the optimal treatment strategy and to develop personalized medicine directly targeting these effects. STUDY FUNDING/COMPETING INTEREST(S) This work was financed by the West China Second University Hospital of Sichuan University (KS369 and KL042). The authors declare that they do not have any conflicts of interests. TRIAL REGISTRATION NUMBER N/A.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
jin1233完成签到 ,获得积分10
7秒前
小马甲应助科研通管家采纳,获得10
14秒前
今后应助科研通管家采纳,获得10
14秒前
爆米花应助科研通管家采纳,获得10
14秒前
坦率的枕头完成签到,获得积分10
40秒前
42秒前
可乐发布了新的文献求助10
45秒前
香蕉觅云应助可乐采纳,获得10
51秒前
1分钟前
Olivia发布了新的文献求助10
1分钟前
Owen应助科研通管家采纳,获得10
2分钟前
科目三应助科研通管家采纳,获得10
2分钟前
Olivia完成签到,获得积分20
3分钟前
3分钟前
平淡幻枫发布了新的文献求助10
3分钟前
Owen应助平淡幻枫采纳,获得10
3分钟前
lll完成签到,获得积分10
3分钟前
lll发布了新的文献求助10
3分钟前
上官若男应助lll采纳,获得10
4分钟前
深情安青应助科研通管家采纳,获得10
4分钟前
Mindray完成签到,获得积分10
4分钟前
小汤完成签到 ,获得积分10
4分钟前
5分钟前
wangnn发布了新的文献求助30
5分钟前
wangnn完成签到,获得积分10
6分钟前
SciGPT应助科研通管家采纳,获得10
6分钟前
隐形曼青应助江彪采纳,获得10
6分钟前
6分钟前
江彪发布了新的文献求助10
6分钟前
6分钟前
一剑白完成签到 ,获得积分10
6分钟前
。。完成签到 ,获得积分10
7分钟前
charliechen完成签到 ,获得积分10
7分钟前
传奇完成签到 ,获得积分10
7分钟前
过时的柚子完成签到,获得积分10
8分钟前
8分钟前
NexusExplorer应助科研通管家采纳,获得10
8分钟前
NexusExplorer应助科研通管家采纳,获得10
8分钟前
白华苍松发布了新的文献求助10
8分钟前
JamesPei应助andrele采纳,获得10
8分钟前
高分求助中
Sustainability in Tides Chemistry 2800
The Young builders of New china : the visit of the delegation of the WFDY to the Chinese People's Republic 1000
Rechtsphilosophie 1000
Bayesian Models of Cognition:Reverse Engineering the Mind 888
Le dégorgement réflexe des Acridiens 800
Defense against predation 800
Very-high-order BVD Schemes Using β-variable THINC Method 568
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3137011
求助须知:如何正确求助?哪些是违规求助? 2787960
关于积分的说明 7784196
捐赠科研通 2444060
什么是DOI,文献DOI怎么找? 1299705
科研通“疑难数据库(出版商)”最低求助积分说明 625497
版权声明 600997