Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; Section of Endocrinology Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL, USA.
Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Best Pract Res Clin Endocrinol Metab. 2022 Jan;36(1):101594. doi: 10.1016/j.beem.2021.101594. Epub 2021 Oct 14.
Primary ovarian insufficiency (POI) is determined by exhaustion of follicles in the ovaries, which leads to infertility before the age of 40 years. It is characterized by a strong familial and heterogeneous genetic background. Therefore, we will mainly discuss the genetic basis of POI in this review. We identified 107 genes related to POI etiology in mammals described by several independent groups. Thirty-four of these genes (AARS2, AIRE, ANTXR1, ATM, BMPR1B, CLPP, CYP17A1, CYP19A1, DCAF17, EIF2B, ERAL1, FANCA, FANCC, FMR1, FOXL2, GALT, GNAS, HARS2, HSD17B4, LARS2, LMNA, MGME1, NBN, PMM2, POLG, PREPL, RCBTB1, RECQL2/3/4, STAR, TWNK, and XRCC4/9) have been linked to syndromic POI and are mainly implicated in metabolism function and meiosis/DNA repair. In addition, the majority of genes associated with nonsyndromic POI, widely expanded by high-throughput techniques over the last decade, have been implicated in ovarian development and meiosis/DNA repair pathways (ATG7, ATG9, ANKRD31, BMP8B, BMP15, BMPR1A, BMPR1B, BMPR2, BNC1, BRCA2, CPEB1, C14ORF39, DAZL, DIAPH2, DMC1, ERCC6, FANCL, FANCM, FIGLA, FSHR, GATA4, GDF9, GJA4, HELQ, HSF2BP, HFM1, INSL3, LHCGR, LHX8, MCM8, MCM9, MEIOB, MSH4, MSH5, NANOS3, NOBOX, NOTCH2, NR5A1, NUP107, PGRMC1, POLR3H, PRDM1, PRDM9, PSMC3IP, SOHLH1, SOHLH2, SPIDR, STAG3, SYCE1, TP63, UBR2, WDR62, and XRCC2), whereas a few are related to metabolic functions (EIF4ENIF1, KHDRBS1, MRPS22, POLR2C). Some genes, such as STRA8, FOXO3A, KIT, KITL, WNT4, and FANCE, have been shown to cause ovarian insufficiency in rodents, but mutations in these genes have yet to be elucidated in women affected by POI. Lastly, some genes have been rarely implicated in its etiology (AMH, AMHR2, ERRC2, ESR1, INHA, LMN4, POF1B, POU5F1, REC8, SMC1B). Considering the heterogeneous genetic and familial background of this disorder, we hope that an overview of literature data would reinforce that genetic screening of those patients is worthwhile and helpful for better genetic counseling and patient management.
原发性卵巢功能不全（POI）是由卵巢中卵泡耗竭引起的，导致 40 岁以前不孕。其特征是具有强烈的家族性和异质性遗传背景。因此，我们将主要讨论该综述中 POI 的遗传基础。我们鉴定了哺乳动物中由几个独立小组描述的与 POI 病因相关的 107 个基因。其中 34 个基因（AARS2、AIRE、ANTXR1、ATM、BMPR1B、CLPP、CYP17A1、CYP19A1、DCAF17、EIF2B、ERAL1、FANCA、FANCC、FMR1、FOXL2、GALT、GNAS、HARS2、HSD17B4、LARS2、LMNA、MGME1、NBN、PMM2、POLG、PREPL、RCBTB1、RECQL2/3/4、STAR、TWNK 和 XRCC4/9）与综合征性 POI 相关，主要涉及代谢功能和减数分裂/DNA 修复。此外，与非综合征性 POI 相关的大多数基因（通过过去十年的高通量技术广泛扩展）与卵巢发育和减数分裂/DNA 修复途径有关（ATG7、ATG9、ANKRD31、BMP8B、BMP15、BMPR1A、BMPR1B、BMPR2、BNC1、BRCA2、CPEB1、C14ORF39、DAZL、DIAPH2、DMC1、ERCC6、FANCL、FANCM、FIGLA、FSHR、GATA4、GDF9、GJA4、HELQ、HSF2BP、HFM1、INSL3、LHCGR、LHX8、MCM8、MCM9、MEIOB、MSH4、MSH5、NANOS3、NOBOX、NOTCH2、NR5A1、NUP107、PGRMC1、POLR3H、PRDM1、PRDM9、PSMC3IP、SOHLH1、SOHLH2、SPIDR、STAG3、SYCE1、TP63、UBR2、WDR62 和 XRCC2），而少数与代谢功能有关（EIF4ENIF1、KHDRBS1、MRPS22、POLR2C）。一些基因，如 STRA8、FOXO3A、KIT、KITL、WNT4 和 FANCE，已被证明在啮齿动物中引起卵巢功能不全，但这些基因的突变在 POI 患者中尚未阐明。最后，一些基因很少与病因有关（AMH、AMHR2、ERRC2、ESR1、INHA、LMN4、POF1B、POU5F1、REC8、SMC1B）。鉴于该疾病的遗传和家族背景存在异质性，我们希望文献数据的概述将加强遗传筛选对这些患者的价值，并有助于更好的遗传咨询和患者管理。
