Genetics of ovarian insufficiency and defects of folliculogenesis

• Published in: Baillière's best practice & research. Clinical endocrinology & metabolism Vol. 36; no. 1; p. 101594
• Main Authors: França, Monica Malheiros, Mendonca, Berenice Bilharinho
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.01.2022
• Subjects: Adaptor Proteins, Signal Transducing; Amino Acyl-tRNA Synthetases; Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Cycle Proteins; DNA Helicases; DNA-Binding Proteins - genetics; Exodeoxyribonucleases; Female; Fragile X Mental Retardation Protein; genetic etiology; Genetic Testing; Guanine Nucleotide Exchange Factors; Histone-Lysine N-Methyltransferase; Humans; infertility; Mammals - genetics; Membrane Proteins - genetics; Microfilament Proteins - genetics; Mutation; Nerve Tissue Proteins; next-generation sequencing; Nuclear Proteins - genetics; ovarian development; Ovarian Diseases; primary ovarian insufficiency; Primary Ovarian Insufficiency - genetics; Receptors, Cell Surface; Receptors, Progesterone; RNA-Binding Proteins; Trans-Activators - genetics; Ubiquitin-Protein Ligase Complexes; primary ovarian insufficiency; ovarian development; genetic etiology; infertility; next-generation sequencing
• ISSN: 1521-690X; 1878-1594
• DOI: 10.1016/j.beem.2021.101594

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.