TRIP13基因新突变导致卵母细胞成熟阻滞为特征的女性不孕

doi:10.16288/j.yczz.23-022

遗传 ›› 2023, Vol. 45 ›› Issue (6): 514-525.doi: 10.16288/j.yczz.23-022

TRIP13基因新突变导致卵母细胞成熟阻滞为特征的女性不孕

吕香江¹(), 郭静²(), 林戈^1,²()

1.中南大学基础医学院生殖与干细胞工程研究所，长沙 410078
2.中信湘雅生殖与遗传专科医院，长沙 410008

收稿日期:2023-02-01 修回日期:2023-03-30 出版日期:2023-06-20 发布日期:2023-04-21
通讯作者: 郭静,林戈 E-mail:lvxiangjiang@163.com;linggf@hotmail.com;815457238@qq.com
作者简介:吕香江，在读硕士研究生，专业方向：遗传学。E-mail：lvxiangjiang@163.com
基金资助:
国家自然科学基金项目(81901473);中信湘雅生殖遗传专科医院院内项目(YNXM-201810)

Novel mutations in TRIP13 lead to female infertility with oocyte maturation arrest

Xiangjiang Lv¹(), Jing Guo²(), Ge Lin^1,²()

1. Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha 410078, China
2. Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha 410008, China

Received:2023-02-01 Revised:2023-03-30 Online:2023-06-20 Published:2023-04-21
Contact: Guo Jing,Lin Ge E-mail:lvxiangjiang@163.com;linggf@hotmail.com;815457238@qq.com
Supported by:
National Natural Science Foundation of China(81901473);Scientific Research Foundation of Reproductive and Genetic Hospital of China International Trust Investment Corporation (CITIC) Xiangya(YNXM-201810)

摘要/Abstract

摘要：

卵母细胞成熟阻滞(oocyte maturation arrest，OMA)是指卵母细胞减数分裂过程异常而导致的卵母细胞成熟障碍的一种罕见的临床现象，也是女性原发性不孕的原因之一。这类患者临床上常表现为：反复促排卵后无法获得成熟卵子，并且未成熟卵母细胞经体外培养后仍不能成熟。迄今研究发现PATL2、TUBB8和TRIP13基因突变与OMA有关，但是有关OMA的遗传学分子因素及机制研究仍不完整。本研究通过收集临床上辅助生殖助孕过程中35名反复出现OMA的原发不孕女性患者的外周血，提取其基因组DNA进行全外显子组测序分析，对疑似致病突变进行验证及家系共分离分析，发现先证者1的TRIP13基因9号外显子存在纯合突变c.859A>G，突变导致对应编码的287位的氨基酸由异亮氨酸突变为缬氨酸(p.Ile287Val)；先证者2的TRIP13基因1号外显子存在纯合突变c.77A>G，突变导致对应编码的26位的氨基酸由组氨酸突变为精氨酸(p.His26Arg)；先证者3的TRIP13基因的4号和12号外显子存在复合杂合突变c.409G>A和c.1150A>G，c.409G>A突变导致对应编码的137位的氨基酸由天冬氨酸突变为天冬酰胺(p.Asp137Asn)，c.1150A>G突变导致对应编码的384位的氨基酸由丝氨酸突变为甘氨酸(p.Ser384Gly)，三名患者所携带的突变均引起TRIP13基因编码的TRIP13蛋白发生错义突变。其中3个突变位点在国内外尚未有文献报道。此外，通过在HeLa细胞中分别转染四个突变质粒，并进行体外免疫印记实验和细胞增殖实验，发现这些突变会造成不同程度的TRIP13蛋白表达的增加以及细胞增殖速率异常。本文总结了既往研究报道的TRIP13基因突变位点，丰富了TRIP13致病基因突变谱，为进一步研究TRIP13基因导致OMA的致病机制及临床的诊断和治疗提供了依据。

关键词: 卵母细胞成熟阻滞, TRIP13, 减数分裂, 女性不孕

Abstract:

Oocyte maturation arrest (OMA) refers to a rare clinical phenomenon of oocyte maturation disorder caused by abnormal meiosis, which is also one of the primary causes of female infertility. The clinical manifestations of these patients are often characterized with failure to obtain mature oocytes after repeated ovulation stimulation and/or induced in vitro maturation. To date, mutations in PATL2, TUBB8 and TRIP13 have been demonstrated to be associated with OMA, but studies on the genetic-based factors and mechanisms of OMA are still incomplete. In this study, peripheral blood from 35 primary infertile women characterized with recurrent OMA during assisted reproductive technology (ART) were subjected to whole-exome sequencing (WES). By using Sanger sequencing and co-segregated analysis, we identified four pathogenic variants in TRIP13. Proband 1 had a homozygous missense mutation of c.859A>G appeared on the 9th exon, which resulted in substitution of Ile287 to valine (p.Ile287Val); proband 2 had a homozygous missense mutation of c.77A>G on the 1st exon, which resulted in substitution of His26 to arginine (p.His26Arg); and proband 3 had compound heterozygous mutations of c.409G>A and c.1150A>G on the 4th and 12th exon, which resulted in the substitutions of Asp137 to asparagine (p.Asp137Asn) and Ser384 to glycine (p.Ser384Gly) in the encoded protein respectively. Three of these mutations have not been reported previously. Further, transfection of plasmids harboring the respective mutated TRIP13 in HeLa cells resulted in changes in TRIP13 expression and abnormal cell proliferation as demonstrated by western blotting and cell proliferation assay respectively. This study further summarizes the TRIP13 mutations reported previously and expands the mutation spectrum of TRIP13 pathogenic variants, thereby providing a valuable reference for further research on the pathogenic mechanism of OMA associated with TRIP13 mutations.

Key words: oocyte maturation arrest, TRIP13, meiosis, female infertility

吕香江, 郭静, 林戈. TRIP13基因新突变导致卵母细胞成熟阻滞为特征的女性不孕[J]. 遗传, 2023, 45(6): 514-525.

Xiangjiang Lv, Jing Guo, Ge Lin. Novel mutations in TRIP13 lead to female infertility with oocyte maturation arrest[J]. Hereditas(Beijing), 2023, 45(6): 514-525.

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家族编号	患者年龄	不孕时间	促排方案	IVF/ICSI	获卵数	未成熟卵(GV/MI)	MII卵
1	28	8	降调节短效长方案	ICSI	17	14	0
2	30	4	降调节短效长方案	IVF	2	2	0
			降调节短效长方案	IVF	11	10	1
			拮抗剂方案	ICSI	7	7	0
3	29	2	拮抗剂方案	IVF	21	19	2
3	29	2	拮抗剂方案	IVF	23	23	0

家族编号	突变位点	变异评级(ACMG分级)^*	REVEL	PolyPhen2	Mutation Taste
1	c.859A>G(p.Ile287Val)	临床意义未明变异(PM1+PM2+PP3)	0.687	可能致病	致病
2	c.77A>G(p.His26Arg)	致病(PM2+PP5+BP1+BP4)	0.17	良性	致病
3	c.409G>A(p.Asp137Asn)	临床意义未明变异(PM2+PP3)	0.616	良性	致病
3	c.1150A>G(p.Ser384Gly)	临床意义未明变异(PM2+PP3)	0.823	可能致病	致病

TRIP13基因新突变导致卵母细胞成熟阻滞为特征的女性不孕

Novel mutations in TRIP13 lead to female infertility with oocyte maturation arrest

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家族编号	突变位点的物理位置	外显子	cDNA的变化	氨基酸的变化	突变类型	基因型
1	Chr5:908569	9	c.859A>G	p.Ile287Val	错义突变	纯合
2	Chr5:893190	1	c.77A>G	p.His26Arg	错义突变	纯合
3	Chr5:900629	4	c.409G>A	p.Asp137Asn	错义突变	复合杂合
3	Chr5:916035	12	c.1150A>G	p.Ser384Gly	错义突变	复合杂合

外显子	cDNA的变化	氨基酸的变化	突变类型	基因型	疾病类型	参考文献
-	c.673-1G>C	-	剪接突变	纯合	肾母细胞瘤	[18]
11	c.1060C>T	p.Arg354*	无义突变	纯合	肾母细胞瘤	[18]
1	c.77A>G	p.His26Arg	错义突变	纯合	女性不孕症(卵母细胞成熟阻滞)	[6]
5	c.518G>A	p.Arg173Gln	错义突变	复合杂合	女性不孕症(卵母细胞成熟阻滞)	[6]
6	c.592A>G	p.Ile198Val	错义突变	复合杂合	女性不孕症(卵母细胞成熟阻滞)	[6]
8	c.739G>A	p.Val247Met	错义突变	复合杂合	女性不孕症(卵母细胞成熟阻滞)	[6]
10	c.907G>A	p.Glu303Lys	错义突变	复合杂合	女性不孕症(卵母细胞成熟阻滞)	[6]
1	c.77A>G	p.His26Arg	错义突变	复合杂合	女性不孕症(合子卵裂失败)	[16]
12	c.1141G>A	p.Glu381Lys	错义突变	纯合	女性不孕症(合子卵裂失败)	[16]
13	c.1258A>G	p.Lys420Glu	错义突变	复合杂合	女性不孕症(合子卵裂失败)	[16]
4	c.409G>A	p.Asp137Asn	错义突变	复合杂合	女性不孕症(卵母细胞成熟阻滞)	本研究
9	c.859A>G	p.Ile287Val	错义突变	纯合	女性不孕症(卵母细胞成熟阻滞)	本研究
12	c.1150A>G	p.Ser384Gly	错义突变	复合杂合	女性不孕症(卵母细胞成熟阻滞)	本研究

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