鉴定以卵母细胞成熟停滞为特征的女性不孕症中甲状腺激素受体相互作用蛋白 13 (TRIP13) 的新型剪接变体

IF 4.3 3区材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC ACS Applied Electronic Materials Pub Date : 2024-09-19 DOI:10.1007/s10815-024-03219-1

Jia Chen, Yuxin Liu, Xingwu Wu, Yiwei Zhang, Wen Huang, Wenbo Han, Ge Chen, Qiang Xu, Houyang Chen, Qiongfang Wu, Jiawei Wang, Jialyu Huang

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摘要

目的作为原发性女性不孕症的原因之一，卵母细胞成熟停滞（OMA）的特点是由于减数分裂异常而无法获得成熟的卵母细胞。我们的目的是在一个非近亲结婚的家庭中，在两个具有 OMA 表型的姐妹中找出致病变体。方法我们进行了全外显子组测序和桑格测序，以找出并验证致病基因变体。结果我们在 TRIP13 中发现了一个新的同基因剪接变异（c.1021-11T>C），该变异具有隐性遗传模式。迷你基因测定显示，该变异可破坏 TRIP13 mRNA 的完整性，表现为产生了内含子 10 中间保留 79 bp 的替代转录本。与正常对照组相比，TRIP13 mRNA的表达量和TRIP13蛋白的丰度也明显降低。

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Identification of a novel splicing variant of thyroid hormone receptor interaction protein 13 (TRIP13) in female infertility characterized by oocyte maturation arrest

Purpose

As a cause of primary female infertility, oocyte maturation arrest (OMA) is characterized by failure to obtain mature oocytes due to abnormal meiosis. We aimed to identify pathogenic variants in two sisters with OMA phenotype from a non-consanguineous family.

Methods

Whole-exome sequencing and Sanger sequencing were conducted to identify and validate the disease-causing gene variant. Additionally, we performed a minigene assay, quantitative reverse transcription PCR, and Western blotting to assess the effects of the variant.

Results

We identified a novel homozygous splicing variant (c.1021-11T>C) in TRIP13, which followed a recessive inheritance pattern. Minigene assay showed that the variant could disrupt the integrity of TRIP13 mRNA, as evidenced by the production of an alternative transcript with intron10 intermediate retention of 79 bp. Compared to normal controls, the expression of TRIP13 mRNA and abundance of TRIP13 protein were also significantly decreased in Epstein-Barr virus-immortalized lymphoblastoid cells derived from affected individuals.