Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, 3052, Australia; Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000, Rennes, France; CHU Rennes, Service de Cytogénétique et Biologie Cellulaire, F-35033, Rennes, France.
Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, 3052, Australia.
Maturitas. 2020 Jan;131:78-86. doi: 10.1016/j.maturitas.2019.10.011. Epub 2019 Nov 9.
Ovarian deficiency, including diminished ovarian reserve and premature ovarian insufficiency, represents one of the main causes of female infertility. Little is known of the genetic basis of diminished ovarian reserve, while premature ovarian insufficiency often has a genetic basis, with genes affecting various processes. NR5A1 is a key gene required for gonadal function, and variants are associated with a wide phenotypic spectrum of disorders of sexual development, and are found in 0.26-8% of patients with premature ovarian insufficiency. As there is some debate about the extent of involvement of NR5A1 in the pathogenesis of ovarian deficiency, we performed an in-depth analysis of NR5A1 variants detected in a cohort of 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility associated with normal ovarian function. We identified rare non-synonymous protein-altering variants in 2.8 % of women with ovarian deficiency and no such variants in our small cohort of women with infertility but normal ovarian function. We observed previously reported variants associated with premature ovarian insufficiency in patients with diminished ovarian reserve, highlighting a genetic relationship between these conditions. We confirmed functional impairment resulting from a p.Val15Met variant, detected for the first time in a patient with premature ovarian insufficiency. The remaining variants were associated with preserved transcriptional activity and localization of NR5A1, indicating that rare NR5A1 variants may be incorrectly curated if functional studies are not undertaken, and/or that NR5A1 variants may have only a subtle impact on protein function and/or confer risk of ovarian deficiency via oligogenic inheritance.
卵巢功能不全，包括卵巢储备功能降低和卵巢早衰，是女性不孕的主要原因之一。卵巢储备功能降低的遗传基础知之甚少，而卵巢早衰通常具有遗传基础，影响各种过程的基因。NR5A1 是性腺功能所必需的关键基因，其变体与广泛的性发育障碍表型谱相关，在 0.26-8%的卵巢早衰患者中发现。由于关于 NR5A1 在卵巢功能不全发病机制中的参与程度存在一些争议，我们对 142 例卵巢早衰、卵巢储备功能降低或与正常卵巢功能相关的不明原因不孕患者队列中检测到的 NR5A1 变体进行了深入分析。我们在卵巢功能不全的女性中发现了 2.8%的罕见非同义蛋白改变变体，而在我们的小队列中具有正常卵巢功能的不孕女性中没有发现这种变体。我们观察到与卵巢储备功能降低相关的与卵巢早衰相关的先前报道的变体，突出了这些病症之间的遗传关系。我们证实了 p.Val15Met 变体引起的功能障碍，该变体首次在卵巢早衰患者中检测到。其余变体与 NR5A1 的转录活性和定位保持相关，这表明如果不进行功能研究，罕见的 NR5A1 变体可能被错误地编辑，或者 NR5A1 变体可能对蛋白质功能只有细微影响，并且/或者通过寡基因遗传导致卵巢功能不全的风险。
