Universités Paris Sud, Paris Saclay, Faculté de Médecine; Unité de Génétique Moléculaire des Maladies Métaboliques et de la Reproduction, Hôpitaux Universitaires Paris-Sud, Hôpital Bicêtre AP-HP, Le Kremlin-Bicêtre, France.
Université catholique de Louvain, CHU UCL Namur, Pediatric Endocrinology, Yvoir, Belgium.
J Clin Endocrinol Metab. 2020 Jun 1;105(6). doi: 10.1210/clinem/dgaa155.
Primary Ovarian insufficiency (POI) affects 1% of women aged <40 years and leads most often to definitive infertility with adverse health outcomes. Very recently, genes involved in deoxyribonucleic acid (DNA) repair have been shown to cause POI.
To identify the cause of a familial POI in a consanguineous Turkish family.
Exome sequencing was performed in the proposita and her mother. Chromosomal breaks were studied in lymphoblastoid cell lines treated with mitomycin (MMC).
The proposita presented intrauterine and postnatal growth retardation, multiple pilomatricomas in childhood, and primary amenorrhea. She was treated with growth hormone (GH) from age 14 to 18 years.
We identified a novel nonsense variant in exon 9 of the minichromosome maintenance complex component 8 gene (MCM8) NM_001281522.1: c0.925C > T/p.R309* yielding either a truncated protein or nonsense-mediated messenger ribonucleic acid decay.The variant was homozygous in the daughter and heterozygous in the mother. MMC induced DNA breaks and aberrant metaphases in the patient's lymphoblastoid cells. The mother's cells had intermediate but significantly higher chromosomal breaks compared with a control.
We describe a novel phenotype of syndromic POI related to a novel truncating MCM8 variant. We show for the first time that spontaneous tumors (pilomatricomas) are associated with an MCM8 genetic defect, making the screening of this gene necessary before starting GH therapy in patients with POI with short stature, especially in a familial or consanguineous context. Appropriate familial monitoring in the long term is necessary, and fertility preservation should be considered in heterozygous siblings to avoid rapid follicular atresia.
原发性卵巢功能不全（POI）影响 1%的<40 岁女性，最常导致明确的不孕，并伴有不良健康后果。最近，研究表明参与脱氧核糖核酸（DNA）修复的基因可导致 POI。
鉴定一个土耳其近亲家庭中家族性 POI 的病因。
对先证者及其母亲进行外显子组测序。用丝裂霉素（MMC）处理淋巴母细胞系，研究染色体断裂。
先证者宫内和产后生长迟缓，儿童期多发性毛母细胞瘤，原发性闭经。她从 14 岁到 18 岁接受生长激素（GH）治疗。
我们在微小染色体维持复合物成分 8 基因（MCM8）NM_001281522.1 的exon 9 中发现了一个新的无义变异：c0.925C>T/p.R309*，产生要么是截短蛋白，要么是无义介导的信使核糖核酸降解。该变异在女儿中为纯合子，在母亲中为杂合子。MMC 诱导患者的淋巴母细胞发生 DNA 断裂和异常中期。与对照组相比，母亲的细胞染色体断裂程度居中，但明显更高。
我们描述了一种与新型截断 MCM8 变异相关的综合征性 POI 的新表型。我们首次表明，自发肿瘤（毛母细胞瘤）与 MCM8 遗传缺陷有关，因此在对矮小的 POI 患者开始 GH 治疗之前，特别是在家族性或近亲关系的情况下，有必要筛查该基因。长期进行适当的家族监测是必要的，应考虑对杂合子兄弟姐妹进行生育力保存，以避免卵泡快速闭锁。
