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在 cyclin B3 中存在双等位基因突变与母源减数分裂 II 失败和复发性双雌二倍体三倍体有关。

Biallelic variant in cyclin B3 is associated with failure of maternal meiosis II and recurrent digynic triploidy.

机构信息

Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences (ZUMS), Zanjan, Iran.

Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.

出版信息

J Med Genet. 2021 Nov;58(11):783-788. doi: 10.1136/jmedgenet-2020-106909. Epub 2020 Sep 16.

DOI:10.1136/jmedgenet-2020-106909
PMID:32938693
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8551973/
Abstract

BACKGROUND

Triploidy is one of the most common chromosome abnormalities affecting human gestation and accounts for an important fraction of first-trimester miscarriages. Triploidy has been demonstrated in a few cases of recurrent pregnancy loss (RPL) but its molecular mechanisms are unknown. This study aims to identify the genetic cause of RPL associated with fetus triploidy.

METHODS

We investigated genomic imprinting, genotyped sequence-tagged site (STS) markers and performed exome sequencing in a family including two sisters with RPL. Moreover, we evaluated oocyte maturation in vivo and in vitro and effect of the candidate protein variant in silico.

RESULTS

While features of hydatidiform mole were excluded, the presence of triploidy of maternal origin was demonstrated in the fetuses. Oocyte maturation was deficient and all the maternally inherited pericentromeric STS alleles were homozygous in the fetuses. A deleterious missense variant (p.V1251D) of the cyclin B3 gene () affecting a residue conserved in placental mammals and located in a region that can interact with the cyclin-dependent kinase 1 or cyclin-dependent kinase 2 cosegregated in homozygosity with RPL.

CONCLUSION

Here, we report a family in which a damaging variant in cyclin B3 is associated with the failure of oocyte meiosis II and recurrent fetus triploidy, implicating a rationale for testing in RPL.

摘要

背景

三倍体是影响人类妊娠的最常见染色体异常之一，占早期流产的重要比例。三倍体已在少数复发性妊娠丢失（RPL）病例中得到证实，但其分子机制尚不清楚。本研究旨在鉴定与胎儿三倍体相关的 RPL 的遗传原因。

方法

我们研究了印记基因组、序列标记位点（STS）标记的基因型，并对一个包括两名 RPL 姐妹的家庭进行了外显子组测序。此外，我们评估了体内和体外卵母细胞成熟情况，并在计算机上评估了候选蛋白变异的影响。

结果

尽管排除了葡萄胎的特征，但在胎儿中证实存在母体来源的三倍体。卵母细胞成熟不足，胎儿中所有母体遗传的着丝粒 STS 等位基因均为纯合子。位于与胎盘哺乳动物保守的残基处并位于可与细胞周期蛋白依赖性激酶 1 或细胞周期蛋白依赖性激酶 2 相互作用的区域的 cyclin B3 基因的有害错义变异（p.V1251D）（）与 RPL 共分离。

结论

在这里，我们报告了一个家族，其中 cyclin B3 中的有害变异与卵母细胞减数分裂 II 失败和复发性胎儿三倍体有关，这为 RPL 的测试提供了合理的依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c02a/8551973/5cccea0609ce/jmedgenet-2020-106909f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c02a/8551973/c6596ebb731c/jmedgenet-2020-106909f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c02a/8551973/b0bfbf598950/jmedgenet-2020-106909f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c02a/8551973/5cccea0609ce/jmedgenet-2020-106909f03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c02a/8551973/c6596ebb731c/jmedgenet-2020-106909f01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c02a/8551973/b0bfbf598950/jmedgenet-2020-106909f02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c02a/8551973/5cccea0609ce/jmedgenet-2020-106909f03.jpg

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