Novel loss-of-function mutation in MCM8 causes premature ovarian insufficiency
Novel loss-of-function mutation in MCM8 causes premature ovarian insufficiency
复制标题
MCM8 的新型功能丧失突变导致卵巢早衰
DOI：
10.1002/mgg3.1165
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发表时间：
2020-04-01
影响因子：
2
通讯作者：
Tan, Yue-Qiu
中科院分区：
文献类型：
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作者：
Zhang, Ya-Xin;He, Wen-Bin;Tan, Yue-Qiu
背景卵巢功能不全(POI)是女性不孕症的主要原因之一，微小染色体维持复合体8(MCM8)已被报道与POI有关。用Sanger测序验证所有家系成员的变异体。应用多种生物信息学软件进行致病性评价。结果在患者中发现了一种新的MCM8基因移码突变(NM_032485.4：C.351delAAAG)，并与该家系中的POI分离。据预测，这种突变会产生截短的MCM8蛋白，并具有致病性。逆转录聚合酶链式反应显示MCM8基因移码突变导致MCM8转录产物水平显著降低，染色体不稳定性研究表明突变的MCM8修复DNA断裂的能力受损。结论在两例POI患者中发现了一种新的MCM8基因纯合性移码突变，功能分析表明该突变是致病的。我们的发现丰富了MCM8突变谱，可能有助于临床医生做出准确的诊断，从而更好地进行计划生育和遗传咨询。
Background Premature ovarian insufficiency (POI) is one major cause of female infertility, minichromosome maintenance complex component 8 (MCM8) has been reported to be responsible for POI.Methods Whole-exome sequencing was performed to identify the genetic variants of women with POI. Sanger sequencing was used to validate the variants in all the family members. Various bioinformatic software was used for the pathogenicity assessment. Reverse transcription polymerase chain reaction (RT-PCR), real-time quantitative PCR, and a chromosomal instability study induced by mitomycin C were performed to analyze the functional effects of the variant.Results A novel homozygous frameshift mutation (NM_032485.4:c.351_354delAAAG) of MCM8 gene was identified in the patients, segregated with POI in this family. This mutation is predicted to produce truncated MCM8 protein and to be pathogenic. Reverse transcription polymerase chain reaction revealed that the frameshift mutation led to a remarkably reduced level of MCM8 transcript products, and chromosomal instability study showed that the ability of mutant MCM8 to repair DNA breaks was impaired.Conclusion We identified a novel homozygous frameshift mutation in the MCM8 gene in two affected sisters with POI, and functional analysis revealed that this mutation is pathogenic. Our findings enrich the MCM8 mutation spectrum and might help clinicians to make a precise diagnosis, thereby allowing better family planning and genetic counseling.