scholarly journals Pathogenic variants of meiotic double strand break (DSB) formation genes PRDM9 and ANKRD31 in premature ovarian insufficiency

2021 ◽  
Author(s):  
Yiyang Wang ◽  
Ting Guo ◽  
Hanni Ke ◽  
Qian Zhang ◽  
Shan Li ◽  
...  
Keyword(s):  
Ovarian Function ◽  
Primordial Follicle ◽  
Strand Break ◽  
Premature Ovarian Insufficiency ◽  
Dna Double Strand Breaks ◽  
Formation Factor ◽  
Ovarian Insufficiency ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Pathogenic Effects

Abstract Purpose The etiology of premature ovarian insufficiency (POI) is heterogeneous, and genetic factors account for 20–25% of the patients. The primordial follicle pool is determined by the meiosis process, which is initiated by programmed DNA double strand breaks (DSB) and homologous recombination. The objective of the study is to explore the role of DSB formation genes in POI pathogenesis. Methods Variants in DSB formation genes were analyzed from a database of exome sequencing in 1,030 patients with POI. The pathogenic effects of the potentially causative variants were verified by further functional studies. Results Three pathogenic heterozygous variants in PRDM9 and two in ANKRD31 were identified in seven patients. Functional studies showed the variants in PRDM9 impaired its methyltransferase activity, and the ANKRD31 variations disturbed its interaction with another DSB formation factor REC114 by haploinsufficiency effect, indicating the pathogenic effects of the two genes on ovarian function were dosage dependent. Conclusion Our study identified pathogenic variants of PRDM9 and ANKRD31 in POI patients, shedding new light on the contribution of meiotic DSB formation genes in ovarian development, further expanding the genetic architecture of POI.

scholarly journals Meiotic Recombination Defects and Premature Ovarian Insufficiency

2021 ◽  
Vol 9 ◽  
Author(s):  
Chengzi Huang ◽  
Ting Guo ◽  
Yingying Qin
Keyword(s):  
Meiotic Recombination ◽  
Ovarian Function ◽  
Genetic Disorders ◽  
Gene Mutations ◽  
Strand Break ◽  
Premature Ovarian Insufficiency ◽  
Potential Candidate ◽  
Ovarian Insufficiency ◽  
Widespread Application ◽  
Individual Gene

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.

scholarly journals Whole-exome sequencing in patients with premature ovarian insufficiency: early detection and early intervention

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Hongli Liu ◽  
Xiaoli Wei ◽  
Yanwei Sha ◽  
Wensheng Liu ◽  
Haijie Gao ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Ovarian Function ◽  
In Silico Analysis ◽  
Premature Ovarian Insufficiency ◽  
Control Group ◽  
Genetic Etiology ◽  
Ovarian Insufficiency ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Background The loss of ovarian function in women, referred to as premature ovarian insufficiency (POI), is associated with a series of concomitant diseases. POI is genetically heterogeneous, and in most cases, the etiology is unknown. Methods Whole-exome sequencing (WES) was performed on DNA samples obtained from patients with POI, and Sanger sequencing was used to validate the detected potentially pathogenic variants. An in silico analysis was carried out to predict the pathogenicity of the variants. Results We recruited 24 patients with POI and identified variants in POI-related genes in 14 patients, including bi-allelic mutations in DNAH6, HFM1, EIF2B2, BNC, and LRPPRC and heterozygous variants in BNC1, EIF2B4, FOXL2, MCM9, FANCA, ATM, EIF2B3, and GHR. No variants in the above genes were detected in the WES data obtained from 29 women in a control group without POI. Determining a clear genetic etiology could significantly increase patient compliance with appropriate intervention strategies. Conclusions Our study confirmed that POI is a genetically heterogeneous condition and that whole-exome sequencing is a powerful tool for determining its genetic etiology. The results of this study will aid researchers and clinicians in genetic counseling and suggests the potential of WES for the detection of POI and thus early interventions for patients with POI.

scholarly journals Long-term outcome of ovarian function in women with intermittent premature ovarian insufficiency

2016 ◽  
Vol 86 (2) ◽  
pp. 223-228 ◽  
Author(s):  
Anne Bachelot ◽  
Carole Nicolas ◽  
Maud Bidet ◽  
Jérôme Dulon ◽  
Monique Leban ◽  
...  
Keyword(s):  
Ovarian Function ◽  
Premature Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
Term Outcome ◽  
Long Term Outcome

scholarly journals Whole-exome sequencing identifies GPSM1 as a susceptibility gene for premature ovarian insufficiency

2020 ◽  
Author(s):  
Xuzi Cai ◽  
Huijiao Fu ◽  
Yan Wang ◽  
Qiwen Liu ◽  
Xuefeng Wang
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Caspase 3 ◽  
Susceptibility Gene ◽  
Primordial Follicle ◽  
Antral Follicle ◽  
Premature Ovarian Insufficiency ◽  
Protein Signaling ◽  
Ovarian Insufficiency ◽  
Whole Exome

Abstract Background Genetic causes of premature ovarian insufficiency (POI) account for approximately 20~25% of patients. So far, only a few genes have been identified. Results Here, we first identified the c.1840C>A on G-protein signaling modulator 1 (GPSM1) as a susceptibility locus for POI in 10 sporadic POI patients by whole-exome sequencing. The frequency of GPSM1 c.1840C>A was then verified as 3/20 in a POI sample of 20 patients (including the above 10 patients) by Sanger sequencing. RT-PCR and western blot analysis showed the expression of GPSM1 in rat ovaries was increased in the large antral follicle stage compared to the primordial follicle stage (P<0.01). The cell proliferation assay (CCK8) and flow cytometry suggested that the small-interfering RNA-induced silencing of Gpsm1 significantly increased apoptosis and decreased proliferation of rat ovarian granulosa cells (GCs) (P<0.01). Furthermore, suppression of Gpsm1 in GCs reduced levels of cAMP, PKAc, p-CREB as well as the ratio of Bcl-2/Bax, and increased the expression of Caspase-3 and Cleaved Caspase-3 (P<0.01). Conclusions In summary, this study identified a susceptibility variant GPSM1 c.1840C>A of POI for the first time. Gpsm1 was related to rat follicle development, and silencing increased apoptosis and decreased proliferation in rat GCs, possibly through inhibition of the cAMP-PKA-CREB pathway. These findings facilitate the development of the early molecular diagnosis of POI.

scholarly journals Ayurveda management in premature ovarian insufficiency- A case study

2021 ◽  
Vol 5 (2) ◽  
pp. 49-56
Author(s):  
K P Vidya ◽  
Divya U ◽  
Sithara Satheesan
Keyword(s):  
Ovarian Function ◽  
Single Case ◽  
Hot Flashes ◽  
Signs And Symptoms ◽  
Premature Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
Post Evaluation ◽  
Related Quality ◽  
Health Related

Premature ovarian insufficiency (POI) is defined as a cessation of ovarian function before the age of 40 years. It is associated with hypoestrogenism and loss of residual follicles, both of which lead to menstrual abnormalities, pregnancy failures, and decreased health-related quality of life. The prevalence of POI is estimated at 1% in the general population. The risk of premature ovarian insufficiency (POI) before the age of 40 years is 1 %. The aetiopathology of premature ovarian insufficiency in the majority of cases is unknown and is termed as spontaneous or idiopathic POI. This is a case with signs and symptoms of POI which was developed after the administration of GnRH agonist drugs as a part of treatment of endometriosis. In this single case study, a female of 33 years having complaints of absence of periods since 6 months treated with Ayurveda treatment with pre and post evaluation. The symptoms of secondary amenorrhoea, hot flashes, vaginal dryness and mood swings were relieved after Ayurveda medications and procedures.

scholarly journals Genetics of premature ovarian insufficiency and the association with X-autosome translocations

Reproduction ◽  
2020 ◽  
Vol 160 (4) ◽  
pp. R55-R64
Author(s):  
Adriana Di-Battista ◽  
Mariana Moysés-Oliveira ◽  
Maria Isabel Melaragno
Keyword(s):  
X Chromosome ◽  
Molecular Mechanisms ◽  
Ovarian Function ◽  
Single Gene ◽  
Position Effect ◽  
Gene Mutations ◽  
Premature Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
Functional Consequences ◽  
Critical Regions

Premature ovarian insufficiency (POI) is the cessation of menstruation before the age of 40 and can result from different etiologies, including genetic, autoimmune, and iatrogenic. Of the genetic causes, single-gene mutations and cytogenetic alterations, such as X-chromosome aneuploidies and chromosome rearrangements, can be associated with POI. In this review, we summarize the genetic factors linked to POI and list the main candidate genes. We discuss the association of these genes with the ovarian development, the functional consequences of different mutational mechanisms and biological processes that are frequently disrupted during POI pathogenesis. Additionally, we focus on the high prevalence of X-autosome translocations involving the critical regions in Xq, known as POI1 and POI2, and discuss in depth the main hypotheses proposed to explain this association. Although the incorrect pairing of chromosomes during meiosis could lead to oocyte apoptosis, the reason for the prevalence of X-chromosome breakpoints at specific regions remains unclear. In most cases, studies on genes disrupted by balanced structural rearrangements cannot explain the ovarian failure. Thus, the position effect has emerged as a putative explanation for genetic mechanisms as translocations possibly result in changes in overall chromatin topology due to chromosome repositioning. Given the tremendous impact of POI on women’s quality of life, we highlight the value of investigations in to the interplay between ovarian function and gene regulation to deepen our understanding of the molecular mechanisms related to this disease, with the ultimate goal of improving patients’ care and assistance.

scholarly journals Premature Ovarian Insufficiency - an update on recent advances in understanding and management

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2069 ◽  
Author(s):  
Saioa Torrealday ◽  
Pinar Kodaman ◽  
Lubna Pal
Keyword(s):  
Ovarian Function ◽  
Clinical Medicine ◽  
Premature Ovarian Insufficiency ◽  
Clear Understanding ◽  
Timely Manner ◽  
Ovarian Insufficiency ◽  
Ongoing Research ◽  
Health Complications

Premature ovarian insufficiency is a complex and relatively poorly understood entity with a myriad of etiologies and multisystem sequelae that stem from premature deprivation of ovarian sex hormones. Timely diagnosis with a clear understanding of the various comorbidities that can arise from estrogen deficiency is vital to appropriately counsel and treat these patients. Prompt initiation of hormone therapy is critical to control the unsolicited menopausal symptoms that many women experience and to prevent long-term health complications. Despite ongoing efforts at improving our understanding of the mechanisms involved, any advancement in the field in recent decades has been modest at best and researchers remain thwarted by the complexity and heterogeneity of the underpinnings of this entity. In contrast, the practice of clinical medicine has made meaningful strides in providing assurance to the women with premature ovarian insufficiency that their quality of life as well as long-term health can be optimized through timely intervention. Ongoing research is clearly needed to allow pre-emptive identification of the at-risk population and to identify mechanisms that if addressed in a timely manner, can prolong ovarian function and physiology.

Premature ovarian insufficiency: Genetic causes and treatment options. A literature review

2021 ◽  
Vol 70 (3) ◽  
pp. 75-91
Author(s):  
Valentina M. Denisova ◽  
Maria I. Yarmolinskaya ◽  
Karina A. Zakurayeva
Keyword(s):  
Literature Review ◽  
Ovarian Function ◽  
Treatment Options ◽  
Clinical Signs ◽  
Premature Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
Diagnostic Features ◽  
Genetic Causes ◽  
Pubmed Database

Premature ovarian insufficiency is a syndrome characterized by hypergonadotropic ovarian insufficiency and the reduction of ovarian function before age 40. This leads to reproductive failures, metabolic changes, and a decrease in quality of life. Currently, occult and initial forms of premature ovarian insufficiency, which have their own diagnostic features and management tactics, can be figured out. The frequency of this syndrome is between 1.1 and 3.7% and the tendency for incidence to increase can be seen. This article is a literature review of the data available in the PubMed database (20052020), with international clinical guidelines taken into consideration. The genetic causes of premature ovarian insufficiency, clinical signs of this pathology and treatments options for such patients are included into the review. In addition, some features of assisted reproductive technology within this group are described.

Variations of C14ORF39 and SYCE1 identified in idiopathic premature ovarian insufficiency and nonobstructive azoospermia

2021 ◽  
Author(s):  
Dong Hou ◽  
Chencheng Yao ◽  
Bingying Xu ◽  
Wei Luo ◽  
Hanni Ke ◽  
...  
Keyword(s):  
Outcome Measure ◽  
Premature Ovarian Insufficiency ◽  
Functional Study ◽  
Nonobstructive Azoospermia ◽  
Ovarian Insufficiency ◽  
Functional Studies ◽  
Whole Exome ◽  
Inheritance Mode ◽  
Genetics And Genomics

Abstract Context Premature ovarian insufficiency (POI) and nonobstructive azoospermia (NOA) are the most sever disease causing irreversible infertility in female and male respectively. The contribution of synaptonemal complex (SC) genes variations in the pathogenesis of sporadic patients with POI and NOA has not been systematically illustrated. Objective To investigate the role of SC genes in the pathogenesis of sporadic POI and NOA. Design Genetic and functional study. Setting University-based reproductive medicine center. Patient(s) A total of 1,030 patients with sporadic POI and 400 patients with sporadic NOA. Intervention(s) The variations of SC genes were filtered in the in-house database of whole exome sequencing performed in 1,030 patients with sporadic POI and 400 patients with sporadic NOA. The pathogenic or likely pathogenic variations following recessive inheritance mode were selected according to American College of Medical Genetics and Genomics (ACMG) guidelines and confirmed by Sanger sequencing. The pathogenic effects of the variations were verified by functional studies. Main Outcome Measure(s) ACMG classification and functional characteristics. Result(s) Two homozygous variations of C14ORF39 and two recessive variations of SYCE1 were firstly identified in sporadic patients with POI and NOA respectively. Functional studies showed the C14ORF39 variations significantly accelerated the protein degradation, and the variations in SYCE1 disrupted its interaction with SYCP1 or C14ORF39, both of which affected SC assembly and meiosis. Conclusion(s) Our study identified novel pathogenic variations of C14ORF39 and SYCE1 in sporadic patients with POI or NOA, highlighting the essential role of SC genes in the maintenance of ovarian and testicular function.

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