scholarly journals Premature Ovarian Insufficiency: New Perspectives on Genetic Cause and Phenotypic Spectrum

2016 ◽  
Vol 37 (6) ◽  
pp. 609-635 ◽  
Author(s):  
Elena J. Tucker ◽  
Sonia R. Grover ◽  
Anne Bachelot ◽  
Philippe Touraine ◽  
Andrew H. Sinclair
Keyword(s):  
Mouse Models ◽  
Genetic Basis ◽  
Current Knowledge ◽  
Premature Ovarian Insufficiency ◽  
Ovarian Activity ◽  
Substantial Evidence ◽  
Ovarian Insufficiency ◽  
Phenotypic Spectrum ◽  
Disease Mechanisms

Abstract Premature ovarian insufficiency (POI) is one form of female infertility, defined by loss of ovarian activity before the age of 40 and characterized by amenorrhea (primary or secondary) with raised gonadotropins and low estradiol. POI affects up to one in 100 females, including one in 1000 before the age of 30. Substantial evidence suggests a genetic basis for POI; however, the majority of cases remain unexplained, indicating that genes likely to be associated with this condition are yet to be discovered. This review discusses the current knowledge of the genetic basis of POI. We highlight genes typically known to cause syndromic POI that can be responsible for isolated POI. The role of mouse models in understanding POI pathogenesis is discussed, and a thorough list of candidate POI genes is provided. Identifying a genetic basis for POI has multiple advantages, such as enabling the identification of presymptomatic family members who can be offered counseling and cryopreservation of eggs before depletion, enabling personalized treatment based on the cause of an individual's condition, and providing better understanding of disease mechanisms that ultimately aid the development of improved treatments.

scholarly journals Long noncoding RNA HCP5 participates in premature ovarian insufficiency by transcriptionally regulating MSH5 and DNA damage repair via YB1

2020 ◽  
Vol 48 (8) ◽  
pp. 4480-4491 ◽  
Author(s):  
Xiaoyan Wang ◽  
Xinyue Zhang ◽  
Yujie Dang ◽  
Duan Li ◽  
Gang Lu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Noncoding Rna ◽  
Dna Damage Repair ◽  
Noncoding Rnas ◽  
Epigenetic Mechanism ◽  
Premature Ovarian Insufficiency ◽  
Genetic Etiology ◽  
Ovarian Insufficiency ◽  
Damage Repair

Abstract The genetic etiology of premature ovarian insufficiency (POI) has been well established to date, however, the role of long noncoding RNAs (lncRNAs) in POI is largely unknown. In this study, we identified a down-expressed lncRNA HCP5 in granulosa cells (GCs) from biochemical POI (bPOI) patients, which impaired DNA damage repair and promoted apoptosis of GCs. Mechanistically, we discovered that HCP5 stabilized the interaction between YB1 and its partner ILF2, which could mediate YB1 transferring into the nucleus of GCs. HCP5 silencing affected the localization of YB1 into nucleus and reduced the binding of YB1 to the promoter of MSH5 gene, thereby diminishing MSH5 expression. Taken together, we identified that the decreased expression of HCP5 in bPOI contributed to dysfunctional GCs by regulating MSH5 transcription and DNA damage repair via the interaction with YB1, providing a novel epigenetic mechanism for POI pathogenesis.

scholarly journals Neuromuscular and Neuroendocrinological Features Associated With ZC4H2-Related Arthrogryposis Multiplex Congenita in a Sicilian Family: A Case Report

2021 ◽  
Vol 12 ◽  
Author(s):  
Gianluca Piccolo ◽  
Giuseppe d'Annunzio ◽  
Elisabetta Amadori ◽  
Antonella Riva ◽  
Paola Borgia ◽  
...  
Keyword(s):  
Genetic Basis ◽  
First Year ◽  
Arthrogryposis Multiplex Congenita ◽  
Neurodevelopmental Delay ◽  
Pathogenic Variants ◽  
Phenotypic Spectrum ◽  
Distal Muscle ◽  
Neurodevelopmental Impairment ◽  
First Year Of Life

Wieacker-Wolff syndrome (WWS) is an X-linked Arthrogryposis Multiplex Congenita (AMC) disorder associated with broad neurodevelopmental impairment. The genetic basis of WWS lies in hemizygous pathogenic variants in ZC4H2, encoding a C4H2 type zinc-finger nuclear factor abundantly expressed in the developing human brain. The main clinical features described in WWS families carrying ZC4H2 pathogenic variants encompass having a short stature, microcephaly, birth respiratory distress, arthrogryposis, hypotonia, distal muscle weakness, and broad neurodevelopmental delay. We hereby report a Sicilian family with a boy clinically diagnosed with WWS and genetically investigated with exome sequencing (ES), leading to the identification of a c.593G>A (p. R198Q) hemizygous pathogenic variant in the ZC4H2 gene. During the first year of life, the onset of central hypoadrenalism led to recurrent hypoglycemic events, which likely contributed to seizure susceptibility. Also, muscle biopsy studies confirmed a pathology of the muscle tissue and revealed peculiar abnormalities of the neuromuscular junction. In conclusion, we expand the phenotypic spectrum of the WWS-related neurodevelopmental disorders and discuss the role of ZC4H2 in the context of the potential neuroendocrinological and neuromuscular features associated with this condition.

Variants in Homologous Recombination Genes EXO1 and RAD51 Related with Premature Ovarian Insufficiency

2020 ◽  
Vol 105 (10) ◽  
pp. e3566-e3574
Author(s):  
Wei Luo ◽  
Ting Guo ◽  
Guangyu Li ◽  
Ran Liu ◽  
Shidou Zhao ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Budding Yeast ◽  
Protein Localization ◽  
Elevated Serum ◽  
Human Cell Line ◽  
Human Cells ◽  
Premature Ovarian Insufficiency ◽  
Primary Amenorrhea ◽  
Ovarian Insufficiency

Abstract Context Premature ovarian insufficiency (POI) is characterized by cessation of menstruation before 40 years of age and elevated serum level of FSH (>25 IU/L). Recent studies have found a few causative genes responsible for POI enriched in meiotic recombination and DNA damage repair pathways. Objective To investigate the role of variations in homologous recombination genes played in POI pathogenesis. Methods The whole exome sequencing was performed in 50 POI patients with primary amenorrhea. Functional characterizations of the novel variants were carried out in budding yeast and human cell line. Results We identified 8 missense variants in 7 homologous recombination genes, including EXO1, RAD51, RMI1, MSH5, MSH2, MSH6, and MLH1. The mutation p.Thr52Ser in EXO1 impaired the meiotic process of budding yeast and p.Glu68Gly in RAD51-altered protein localization in human cells, both of them impaired the efficiency of homologous recombination repair for DNA double-stranded breaks in human cells. Conclusions Our study first linked the variants of EXO1 and RAD51 with POI and further highlighted the role of DNA repair genes in ovarian dysgenesis.

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.

scholarly journals Kynurenine pathway: the link between depressive disorders and inflammation

2020 ◽  
Vol 74 ◽  
pp. 331-339
Author(s):  
Justyna Kubacka ◽  
Anna Stefańska ◽  
Grażyna Sypniewska
Keyword(s):  
Genetic Basis ◽  
Depressive Disorders ◽  
Genetic Factors ◽  
Current Knowledge ◽  
Kynurenine Pathway ◽  
Major Depression Disorder ◽  
Pathway Activation ◽  
Neuropsychiatric Diseases ◽  
Depression Disorder

Depression is highly prevalent worldwide and the leading cause of disability. It is believed that currently more than 300 million people of all ages suffer from depression. However, the unambiguous cause of the depression remains unknown. It is suggested that the occurrence of this disease is primarily affected by genetic factors, psychological factors and atypical brain structure or function. Recently, an increasingly important role is attributed to the inflammatory response, which is considered to be the main cause of depression. Activation of the kynurenine pathway (KP) is one of the described mechanisms by which inflammation can induce depression. Kynurenine pathway activation is associated with several neuropsychiatric diseases, including major depression disorder (MDD). The imbalance between the neuroprotective and neurotoxic metabolites in the kynurenine pathway and the associated serotonin and melatonin deficiency, may contribute to the manifestation of depressive symptoms. In this review we discuss the role of the major enzymes of the tryptophan KP: tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) and the role of selected kynurenic metabolites in the depressive disorders. Particular attention was also paid to the genetic basis of depressive disorders and to the summary of current knowledge on the effectiveness of treatment and supplementation with tryptophan and 5-hydroxytryptophan in depression.

scholarly journals Rare deleterious BUB1B variants induce premature ovarian insufficiency and early menopause

2020 ◽  
Vol 29 (16) ◽  
pp. 2698-2707 ◽  
Author(s):  
Qing Chen ◽  
Hanni Ke ◽  
Xuezhen Luo ◽  
Lingbo Wang ◽  
Yanhua Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spindle Assembly Checkpoint ◽  
Late Onset ◽  
Missense Variant ◽  
Premature Ovarian Insufficiency ◽  
Ovarian Activity ◽  
Loss Of Function ◽  
Early Menopause ◽  
Ovarian Insufficiency ◽  
Natural Menopause

Abstract Losing of ovarian functions prior to natural menopause age causes female infertility and early menopause. Premature ovarian insufficiency (POI) is defined as the loss of ovarian activity before 40 years of age. Known genetic causes account for 25–30% of POI cases, demonstrating the high genetic heterogeneity of POI and the necessity for further genetic explorations. Here we conducted genetic analyses using whole-exome sequencing in a Chinese non-syndromic POI family with the affected mother and at least four affected daughters. Intriguingly, a rare missense variant of BUB1B c.273A>T (p.Gln91His) was shared by all the cases in this family. Furthermore, our replication study using targeted sequencing revealed a novel stop-gain variant of BUB1B c.1509T>A (p.Cys503*) in one of 200 sporadic POI cases. Both heterozygous BUB1B variants were evaluated to be deleterious by multiple in silico tools. BUB1B encodes BUBR1, a crucial spindle assembly checkpoint component involved in cell division. BUBR1 insufficiency may induce vulnerability to oxidative stress. Therefore, we generated a mouse model with a loss-of-function mutant of Bub1b, and also employed D-galactose-induced aging assays for functional investigations. Notably, Bub1b+/− female mice presented late-onset subfertility, and they were more sensitive to oxidative stress than wild-type female controls, mimicking the clinical phenotypes of POI cases affected by deleterious BUB1B variants. Our findings in human cases and mouse models consistently suggest, for the first time, that heterozygous deleterious variants of BUB1B are involved in late-onset POI and related disorders.

scholarly journals The Role of Noncoding RNA in the Pathophysiology and Treatment of Premature Ovarian Insufficiency

2021 ◽  
Vol 22 (17) ◽  
pp. 9336
Author(s):  
Katarzyna Pankiewicz ◽  
Piotr Laudański ◽  
Tadeusz Issat
Keyword(s):  
Neurological Disorders ◽  
Noncoding Rna ◽  
Ovarian Function ◽  
Hormone Replacement ◽  
Premature Ovarian Insufficiency ◽  
Mineral Density ◽  
Ovarian Insufficiency ◽  
Exosomal Mirnas

Premature ovarian insufficiency (POI) is defined as a loss of ovarian function before the age of 40 years, with a prevalence rate estimated at approximately 1%. It causes infertility and is related to serious long-term health consequences, including reduced life expectancy, increased cardiovascular risk, decreased bone mineral density and neurological disorders. There is currently no effective therapy for POI that is widely available in clinical practice; therefore, the treatment of patients with POI is based on hormone replacement therapy. One of the recent advances in the understanding of the pathophysiology of POI has been the role of microRNAs (miRNAs) and other noncoding RNAs (ncRNAs) in the disease. Moreover, intensive research on human folliculogenesis and reproductive biology has led to the development of novel promising therapeutic strategies with the use of exosomal miRNAs derived from mesenchymal stem cells to restore ovarian function in POI patients. This narrative review focuses on the new studies concerning the role of ncRNAs in the pathogenesis of POI, together with their potential as biomarkers of the disease and targets for therapy.

Sign in / Sign up

Export Citation Format

Share Document