MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency
MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency
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DOI：
10.1210/jc.2016-2565
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发表时间：
2017-02-01
影响因子：
5.8
通讯作者：
Rajkovic, Aleksandar
中科院分区：
文献类型：
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作者：
Desai, Swapna;Wood-Trageser, Michelle;Rajkovic, Aleksandar
目的：评估原发性卵巢功能不全（POI）参与者中微小染色体维持8（MCM 8）和微小染色体维持9（MCM 9）、与MCM 8-MCM 9相关的其他基因和DNA损伤修复（DDR）途径中的变体（包括双等位基因致病性变体）的频率。对POI参与者中的MCM 8、MCM 9和编码与生殖衰老有关的DDR蛋白的基因进行测序。所有患者均在40岁之前被诊断为POI，并表现为卵泡刺激素水平升高。干预措施：无。主要结果测量：未鉴定的MCM 8、MCM 9中的核苷酸变异，以及被认为参与DNA损伤反应途径和/或与生殖衰老有关的基因。结果：MCM 8在155名POI参与者中测序，而MCM 9在151名参与者中测序。155名参与者中有3名（2%）携带可能具有破坏性的杂合MCM 8变异，而151名参与者中有7名（5%）携带可能具有破坏性的杂合MCM 9变异。一名参与者在MCM 9中携带了一种新的纯合变体c.1651C>.T，p.Gln551*，预计该变体将在外显子9中引入一个提前终止密码子。在1名受试者中鉴定出MCM 8和MCM 9中的双等位基因损伤杂合变体。共有10名参与者携带破坏性杂合变异的MCM 8或MCM 9，2个人携带杂合破坏性变异的基因与MCM 8或MCM 9或DDR pathway.Conclusions：我们确定了一个显着的数量潜在的破坏性和新的变异MCM 8和MCM 9参与者POI和检查多等位基因关联与DDR和MCM 8-MCM 9相互作用基因的变异。
Objective: To assess the frequency of variants, including biallelic pathogenic variants, in minichromosome maintenance 8 (MCM8) and minichromosome maintenance 9 (MCM9), other genes related to MCM8-MCM9, and DNA damage repair (DDR) pathway in participants with primary ovarian insufficiency (POI).Design: MCM8, MCM9, and genes encoding DDR proteins that have been implicated in reproductive aging were sequenced among POI participants.Setting: Academic research institution.articipants: All were diagnosed with POI prior to age 40 years and presented with elevated folliclestimulating hormone levels.Interventions: None.Main Outcome Measures: Weidentified nucleotide variants inMCM8, MCM9, and genes thought to be involved in the DNA damage response pathway and/or implicated in reproductive aging.Results: MCM8 was sequenced in 155 POI participants, whereas MCM9 was sequenced in 151 participants. Three of 155 (2%) participants carried possibly damaging heterozygous variants in MCM8, whereas 7 of 151 (5%) individuals carried possibly damaging heterozygous variants in MCM9. One participant carried a novel homozygous variant, c.1651C>.T, p.Gln551*, in MCM9, which is predicted to introduce a premature stop codon in exon 9. Biallelic damaging heterozygous variants in both MCM8 and MCM9 were identified in 1 participant. Of a total of 10 participants carrying damaging heterozygous variants in either MCM8 or MCM9, 2 individuals carried heterozygous damaging variants in genes associated with either MCM8 or MCM9 or the DDR pathway.Conclusions: We identified a significant number of potentially damaging and novel variants in MCM8 and MCM9 among participants with POI and examined multiallelic association with variants in DDR and MCM8-MCM9 interactome genes.