AP-HP, Department of Endocrinology and Reproductive Medicine, Pitié-Salpêtrière Hospital, Reference Center for Rare Endocrine Diseases of Growth, Reference Center for Rare Gynecological Pathologies, F-75013 Paris, France.
National Institute of Health and Medical Research INSERM U1065 - University of Nice-Sophia Antipolis, Mediterranean Center for Molecular Medicine C3M, F-06000 Nice, France.
Int J Mol Med. 2018 Feb;41(2):640-648. doi: 10.3892/ijmm.2017.3257. Epub 2017 Nov 16.
Folliculogenesis requires communication between granulosa cells and oocytes, mediated by connexin-based gap junctions. Connexin 37 (Cx37)-deficient female mice are infertile. The present study assessed Cx37 deficiency in patients with primary ovarian insufficiency (POI). A candidate gene study was performed in patients and controls from the National Genotyping Center (Evry, France) including 58 Caucasian patients with idiopathic isolated POI and 142 Caucasian controls. Direct genomic sequencing of the coding regions of the GJA4 gene (encoding Cx37) was performed with the aim to identify a deleterious variant associated with POI and absent in ethnically matched controls. A single Cx37 variant absent in the control population was identified, namely a c.946G>A heterozygous substitution leading to a p.Gly316Ser variant that was present in two POI patients. This variant was absent in all Caucasian controls from various databases, and has been observed exclusively in African populations. This variant was identified to have a dominant negative effect in HeLa cells in vitro to alter connexon function (by 67.2±7.17%), as determined by Gap-fluorescence recovery after photobleaching. The alteration principally resulted from a decrease of cell surface connexons due to altered trafficking (by 47.73±8.59%). In marked contrast to this observation, a p.Pro258Ser variant frequent in all ethnic populations in databases had no functional effect in vitro. In conclusion, the present study reported on a Cx37 variant in two Caucasian POI patients, which was absent in control Caucasian populations, and which had a deleterious effect in vitro. It is therefore suggested that in the genetic context of the Caucasian population, this variant may contribute to POI.
卵泡发生需要颗粒细胞和卵母细胞之间的通讯，这是由连接蛋白形成的缝隙连接介导的。连接蛋白 37（Cx37）缺陷的雌性小鼠不育。本研究评估了原发性卵巢功能不全（POI）患者中 Cx37 的缺乏情况。在法国埃夫里国家基因分型中心的患者和对照组中进行了候选基因研究，包括 58 名特发性孤立性 POI 的白种人患者和 142 名白种人对照组。目的是确定与 POI 相关且在种族匹配的对照组中不存在的有害变异，对编码 GJA4 基因（编码 Cx37）的编码区进行直接基因组测序。在 POI 患者中发现了一种在对照组中不存在的 Cx37 变体，即 c.946G>A 杂合取代，导致 p.Gly316Ser 变体，该变体存在于两名 POI 患者中。该变体在来自各种数据库的所有白种人对照组中均不存在，并且仅在非洲人群中观察到。该变体在体外通过 HeLa 细胞中的 Gap-fluorescence recovery after photobleaching 确定具有改变连接子功能的显性负效应（减少 67.2±7.17%）。这种改变主要是由于由于运输改变而导致细胞表面连接子减少（减少 47.73±8.59%）。与此观察形成鲜明对比的是，数据库中所有种族群体中常见的 p.Pro258Ser 变体在体外没有功能影响。总之，本研究报道了两名白种人 POI 患者中的 Cx37 变体，该变体在对照组白种人中不存在，并且在体外具有有害影响。因此，在白种人群体的遗传背景下，该变体可能导致 POI。
