ATG7 and ATG9A loss-of-function variants trigger autophagy impairment and ovarian failure
ATG7 and ATG9A loss-of-function variants trigger autophagy impairment and ovarian failure
复制标题
DOI：
10.1038/s41436-018-0287-y
复制
发表时间：
2019-04-01
影响因子：
8.8
通讯作者：
Beau, Isabelle
中科院分区：
文献类型：
--
作者：
Delcour, Clemente;Amazit, Larbi;Beau, Isabelle
目的：原发性卵巢功能不全（POI）是一种常见的疾病，影响40岁以下女性的比例约为1%。POI的特点是卵巢卵泡过早衰竭和血浆促卵泡激素（FSH）水平升高，导致不孕。虽然已经描述了各种病因，包括染色体异常和基因变异，但大多数病例仍然是特发性的。本研究的目的是鉴定和验证导致POI的ATG（自噬相关基因）功能上的新序列变异。方法：我们在计算机上重新分析了先前报道的69名无血缘关系的POI妇女的外显子组测序数据。使用自噬的经典标志，微管相关蛋白1轻链3 β (LC3)进行功能实验，然后将这些基因与溶酶体降解途径联系起来。结果：我们在ATG7和ATG9A变体与POI之间建立了功能联系。我们证明了ATG7和ATG9A变异导致自噬体生物合成减少，从而导致自噬损伤，这是一个与保存形成卵巢储备的原始卵泡有关的关键生物学过程。结论：我们的研究结果揭示了自噬受损是人类POI的一种新的病理生理机制。
Purpose: Primary ovarian insufficiency (POI) is a frequent disorder that affects similar to 1% of women under 40 years of age. POI, which is characterized by the premature depletion of ovarian follicles and elevated plasma levels of follicle-stimulating hormone (FSH), leads to infertility. Although various etiological factors have been described, including chromosomal abnormalities and gene variants, most cases remain idiopathic. The aim of the present study was to identify and validate functionally new sequence variants in ATG (autophagy-related genes) leading to POI.Methods: We have reanalyzed, in silico, the exome sequencing data from a previously reported work performed in 69 unrelated POI women. Functional experiments using a classical hallmark of autophagy, the microtubule-associated protein 1 light chain 3 beta (LC3), were then used to link these genes to this lysosomal degradation pathway.Results: We venture a functional link between ATG7 and ATG9A variants and POI. We demonstrated that variant ATG7 and ATG9A led to a decrease in autophagosome biosynthesis and consequently to an impairment of autophagy, a key biological process implicated in the preservation of the primordial follicles forming the ovarian reserve.Conclusion: Our results unveil that impaired autophagy is a novel pathophysiological mechanism involved in human POI.