Abstract
Premature ovarian insufficiency (POI) is the depletion of ovarian function before 40 years of age due to insufficient oocyte formation or accelerated follicle atresia. Approximately 1–5% of women below 40 years old are affected by POI. The etiology of POI is heterogeneous, including genetic disorders, autoimmune diseases, infection, iatrogenic factors, and environmental toxins. Genetic factors account for 20–25% of patients. However, more than half of the patients were idiopathic. With the widespread application of next-generation sequencing (NGS), the genetic spectrum of POI has been expanded, especially the latest identification in meiosis and DNA repair-related genes. During meiotic prophase I, the key processes include DNA double-strand break (DSB) formation and subsequent homologous recombination (HR), which are essential for chromosome segregation at the first meiotic division and genome diversity of oocytes. Many animal models with defective meiotic recombination present with meiotic arrest, DSB accumulation, and oocyte apoptosis, which are similar to human POI phenotype. In the article, based on different stages of meiotic recombination, including DSB formation, DSB end processing, single-strand invasion, intermediate processing, recombination, and resolution and essential proteins involved in synaptonemal complex (SC), cohesion complex, and fanconi anemia (FA) pathway, we reviewed the individual gene mutations identified in POI patients and the potential candidate genes for POI pathogenesis, which will shed new light on the genetic architecture of POI and facilitate risk prediction, ovarian protection, and early intervention for POI women.
Highlights
Premature ovarian insufficiency (POI) is the depletion or dysfunction of ovarian follicles before the age of 40, which is characterized by menstrual disturbance for at least 4 months, with raised gonadotrophins (FSH > 25 IU/I on two occasions > 4 weeks apart) and estrogen deficiency (European Society for Human et al, 2016)
While only a few genes have been identified with mutations in POI patients, such as MSH4 (Carlosama et al, 2017) and MSH5 (Guo et al, 2017), here, we categorized the genes participating in meiotic homologous recombination (HR), candidate genes for human POI, and further reviewed the mutations in detail, Which have been identified in POI patients (Figure 1 and Table 1)
As an increasing number of women prefer to conceive after their mid-30s, the genetic counseling of POI predisposition will be instructive for their childbearing plans
Summary
Edited by: Wei Li, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences (CAS), China. Reviewed by: Caixia Guo, Key Laboratory of Genome and Precision Medicine, Beijing Institute of Genomics (CAS), China.
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