A rare deleterious missense mutation in the AXIN2 gene in Chinese women with polycystic ovary syndrome.

IF 2 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM
Gynecological Endocrinology Pub Date : 2025-12-01 Epub Date: 2025-02-06 DOI:10.1080/09513590.2025.2463545
Ying Zhang, Yu Chen, Fa-Ying Liu, Jing-Wen Fu, Xian-Xian Liu, Jun Tan, Ou-Ping Huang, Yang Zou
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引用次数: 0

Abstract

Background: Polycystic ovary syndrome (PCOS) is an endocrine disorders and characterized by polycystic ovary morphology and oligomenorrhea, affecting fertility and health condition of female around the world. The causative factors of PCOS are complex, and genetic structure remains a long-standing medical challenge in genetics. Previous genome-wide association study (GWAS) showed that Wing-less-related integration site (Wnt) signaling is the most affected pathway among PCOS-related risk genes, and genetic mutations in the Wnt/β-catenin signaling may lead to abnormal development of PCOS.

Objective: To explore the possibility of axis inhibitor-2 (AXIN2) variants in Chinese women with PCOS and assess their pathogenicities.

Methods: A total of 365 Chinese women with PCOS and 905 women without PCOS as control were recruited from Jiangxi Provincial Maternal and Child Health Hospital, All of the 11 exons and flanking regions of the AXIN2 gene were amplified by polymerase chain reaction (PCR), the potential variants were analyzed by Sanger sequencing. The evolutionary conservation analysis of the identified Axin-2 mutant was analyzed among 15 vertebrates from human to zebrafish. The protein structure change was analyzed between the wild-type and mutation-type. The pathogenicity of AXIN2 variant was further analyzed in silico.

Results: We totally identified 7 genetic variants of AXIN2 in this study, including 4 synonymous and 3 missense. Among them, we find a rare deleterious missense variant [p.R714W (c.2140C > T)]. The allele frequencies of this variant were 0.82% and 0.17% in PCOS cases and matched controls, respectively. And it was ranging from 7.89e-5 to 1.47e-4 in public databases. Fisher's exact test indicated that the allele frequencies in PCOS were p < 0.05 compared to both the controls and the databases. Especially, the mutant amino acid site is highly conserved in vertebrates, while the mutation changed the 714th arginine to tryptophan resulting in significant change in the protein structural of Axin-2.

Conclusion: In this study, we identified a rare deleterious missense AXIN2 mutation [p.R714W (c.2140C > T)] in Chinese women with PCOS, and this mutant is probably pathogenic. This study may provide a new perspective on revealing the genetic variation of PCOS.

中国多囊卵巢综合征妇女中罕见的有害的AXIN2基因错义突变。
背景:多囊卵巢综合征(Polycystic ovarian syndrome, PCOS)是一种以多囊卵巢形态和少月经为特征的内分泌疾病,影响着全世界女性的生育能力和健康状况。多囊卵巢综合征的致病因素是复杂的,遗传结构仍然是一个长期的医学遗传学挑战。既往全基因组关联研究(GWAS)表明,Wnt信号通路是PCOS相关危险基因中受影响最大的通路,Wnt/β-catenin信号通路的基因突变可能导致PCOS的异常发展。目的:探讨轴抑制剂-2 (AXIN2)变异在中国女性PCOS患者中的可能性并评价其致病性。方法:从江西省妇幼保健院招募365名中国PCOS女性和905名非PCOS女性作为对照,采用聚合酶链反应(PCR)扩增AXIN2基因的11个外显子和侧翼区域,采用Sanger测序分析潜在变异。对鉴定的Axin-2突变体在15种脊椎动物(从人到斑马鱼)中的进化保守性进行了分析。分析了野生型和突变型的蛋白结构变化。进一步分析了AXIN2变异的致病性。结果:本研究共鉴定出7个AXIN2基因变异,其中同义变异4个,错义变异3个。其中,我们发现了一种罕见的有害的错义变体[p]。R714W (c.2140C > T)]。该变异在PCOS病例和匹配对照中的等位基因频率分别为0.82%和0.17%。在公共数据库中,其范围为7.89e-5 ~ 1.47e-4。Fisher精确检验显示,PCOS患者的等位基因频率与对照组和数据库相比均为p 0.05。特别是,突变的氨基酸位点在脊椎动物中高度保守,而突变将714号精氨酸变为色氨酸,导致Axin-2蛋白结构发生显著变化。结论:在这项研究中,我们发现了一种罕见的有害错义AXIN2突变[p]。R714W (c.2140C > T)]在中国女性PCOS中存在,该突变体可能具有致病性。本研究为揭示多囊卵巢综合征的遗传变异提供了新的视角。
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来源期刊
Gynecological Endocrinology
Gynecological Endocrinology 医学-妇产科学
CiteScore
4.40
自引率
5.00%
发文量
137
审稿时长
3-6 weeks
期刊介绍: Gynecological Endocrinology , the official journal of the International Society of Gynecological Endocrinology, covers all the experimental, clinical and therapeutic aspects of this ever more important discipline. It includes, amongst others, papers relating to the control and function of the different endocrine glands in females, the effects of reproductive events on the endocrine system, and the consequences of endocrine disorders on reproduction
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