Homozygous mutations in C14orf39/SIX6OS1 cause non-obstructive azoospermia and premature ovarian insufficiency in humans.

Human infertility is a multifactorial disease that affects 8%-12% of reproductive-aged couples worldwide. However, the genetic causes of human infertility are still poorly understood. Synaptonemal complex (SC) is a conserved tripartite structure that holds homologous chromosomes together and plays an indispensable role in the meiotic progression. Here, we identified three homozygous mutations in the SC coding gene C14orf39/SIX6OS1 in infertile individuals from different ethnic populations by whole-exome sequencing (WES). These mutations include a frameshift mutation (c.204_205del [p.His68Glnfs∗2]) from a consanguineous Pakistani family with two males suffering from non-obstructive azoospermia (NOA) and one female diagnosed with premature ovarian insufficiency (POI) as well as a nonsense mutation (c.958G>T [p.Glu320∗]) and a splicing mutation (c.1180-3C>G) in two unrelated Chinese men (individual P3907 and individual P6032, respectively) with meiotic arrest. Mutations in C14orf39 resulted in truncated proteins that retained SYCE1 binding but exhibited impaired polycomplex formation between C14ORF39 and SYCE1. Further cytological analyses of meiosis in germ cells revealed that the affected familial males with the C14orf39 frameshift mutation displayed complete asynapsis between homologous chromosomes, while the affected Chinese men carrying the nonsense or splicing mutation showed incomplete synapsis. The phenotypes of NOA and POI in affected individuals were well recapitulated by Six6os1 mutant mice carrying an analogous mutation. Collectively, our findings in humans and mice highlight the conserved role of C14ORF39/SIX6OS1 in SC assembly and indicate that the homozygous mutations in C14orf39/SIX6OS1 described here are responsible for infertility of these affected individuals, thus expanding our understanding of the genetic basis of human infertility.

Time course changes in in vivo muscle mechanical function and Ca2+ regulation of force following experimentally induced gradual ovarian failure in mice.

The abrupt cessation of ovarian hormone release is associated with declines in muscle contractile function, yet the impact of gradual ovarian failure on muscle contractility across peri-, early- and late-stage menopause remains unclear. In this study, a 4-vinylcyclohexene diepoxide (VCD)-induced ovarian failure mouse model was used to examine time course changes in muscle mechanical function. Plantar flexors of female mice (VCD: n = 10; CON: n = 8) were assessed at 40 (early perimenopause), 80 (late perimenopause), 120 (menopause onset) and 176 (late menopause) days post-initial VCD injection. A torque-frequency relationship was established across a range of frequencies (10-200 Hz). Isotonic dynamic contractions were elicited against relative loads (10-80% maximal isometric torque) to determine the torque-velocity-power relationship. Mice then performed a fatigue task using intermittent 100 Hz isometric contractions until torque dropped by 60%. Recovery of twitch, 10 Hz and 100 Hz torque were tracked for 10 min post-task failure. Additionally, intact muscle fibres from the flexor digitorum brevis underwent a fatigue task (50 repetitions at 70 Hz), and 10 and 100 Hz tetanic [Ca2+] were monitored for 10 min afterward. VCD mice exhibited 16% lower twitch torque than controls across all time points. Apart from twitch torque, 10 Hz torque and 10 Hz tetanic [Ca2+], where VCD showed greater values relative to pre-fatigue during recovery, no significant differences were observed between control and VCD mice during recovery. These results indicate that gradual ovarian failure has minimal detriments to in vivo muscle mechanical function, with minor alterations observed primarily for low-frequency stimulation during recovery from fatigue.

Cellular senescence in the pathogenesis of ovarian dysfunction.

The follicular microenvironment is crucial for normal ovarian function, and intra-ovarian factors, in coordination with gonadotropins, contribute to its regulation. Recent research has revealed that the accumulation of senescent cells worsens the adverse environment of various tissues and plays critical roles in chronological aging and various pathological conditions. Cellular senescence involves cell-cycle arrest, a senescence-associated secretory phenotype (SASP), macromolecular damage, and dysmetabolism. In this review, I summarize the latest knowledge regarding the role of cellular senescence in pathological conditions in the ovary, in the context of reproduction. Specifically, cellular senescence is known to impair follicular and oocyte health in cisplatin- and cyclophosphamide-induced primary ovarian insufficiency and to contribute to the pathogenesis of polycystic ovary syndrome (PCOS). In addition, cellular senescence is induced during the decline in ovarian reserve that is associated with chronological aging, endometriosis, psychological stress, and obesity, but it remains unclear whether it plays a causative role in these conditions. Finally, I discuss the potential for use of cellular senescence as a novel therapeutic target. The modification of SASP using a senomorphic and/or the elimination of senescent cells using a senolytic represent promising therapeutic strategies. Further elucidation of the role of cellular senescence in the effects of various insults on ovarian reserve, including chronological aging, as well as in pathogenesis of ovarian pathologies, including PCOS, may facilitate a new era of reproductive medicine.

Rare deleterious BUB1B variants induce premature ovarian insufficiency and early menopause.

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.

FMR1 expression in human granulosa cells and variable ovarian response: control by epigenetic mechanisms.

In humans, FMR1 (fragile X mental retardation 1) is strongly expressed in granulosa cells (GCs) of the female germline and apparently controls efficiency of folliculogenesis. Major control mechanism(s) of the gene transcription rate seem to be based on the rate of CpG-methylation along the CpG island promoter. Conducting CpG-methylation-specific bisulfite-treated PCR assays and subsequent sequence analyses of both gene alleles, revealed three variably methylated CpG domains (FMR1-VMR (variably methylated region) 1, -2, -3) and one completely unmethylated CpG-region (FMR1-UMR) in this extended FMR1-promoter-region. FMR1-UMR in the core promoter was exclusively present only in female GCs, suggesting expression from both gene alleles, i.e., escaping the female-specific X-inactivation mechanism for the second gene allele. Screening for putative target sites of transcription factors binding with CpG methylation dependence, we identified a target site for the transcriptional activator E2F1 in FMR1-VMR3. Using specific electrophoretic mobility shift assays, we found E2F1 binding efficiency to be dependent on CpG-site methylation in its target sequence. Comparative analysis of these CpGs revealed that CpG 94-methylation in primary GCs of women with normal and reduced efficiency of folliculogenesis statistically significant differences. We therefore conclude that E2F1 binding to FMR1-VMR3 in human GCs is part of an epigenetic mechanism regulating the efficiency of human folliculogenesis. Our data indicate that epigenetic mechanisms may control GC FMR1-expression rates.

Current mechanisms of primordial follicle activation and new strategies for fertility preservation.

Premature ovarian insufficiency (POI) is characterized by symptoms caused by ovarian dysfunction in patients aged <40 years. It is associated with a shortened reproductive lifespan. The only effective treatment for patients who are eager to become pregnant is IVF/Embryo Transfer (ET) using oocytes donated by young women. However, the use of the technique is constrained by the limited supply of oocytes and ethical issues. Some patients with POI still have some residual follicles in the ovarian cortex, which are not regulated by gonadotropin. These follicles are dormant. Therefore, activating dormant primordial follicles (PFs) to obtain high-quality oocytes for assisted reproductive technology may bring new hope for patients with POI. Therefore, this study aimed to explore the factors related to PF activation, such as the intercellular signaling network, the internal microenvironment of the ovary and the environment of the organism. In addition, we discussed new strategies for fertility preservation, such as in vitro activation and stem cell transplantation.

Premature ovarian ageing following heterozygous loss of Senataxin.

Premature loss of ovarian activity before 40 years of age is known as primary ovarian insufficiency (POI) and occurs in ∼1% of women. A more subtle decline in ovarian activity, known as premature ovarian ageing (POA), occurs in ∼10% of women. Despite the high prevalence of POA, very little is known regarding its genetic causation. Senataxin (SETX) is an RNA/DNA helicase involved in repair of oxidative stress-induced DNA damage. Homozygous mutation of SETX leads to the neurodegenerative disorder, ataxia oculomotor apraxia type 2 (AOA2). There have been reports of POI in AOA2 females suggesting a link between SETX and ovarian ageing. Here, we studied female mice lacking either one (Setx+/-) or both (Setx-/-) copies of SETX over a 12- to 14-month period. We find that DNA damage is increased in oocytes from 8-month-old Setx+/- and Setx-/- females compared with Setx+/+ oocytes leading to a marked reduction in all classes of ovarian follicles at least 4 months earlier than typically occurs in female mice. Furthermore, during a 12-month long mating trial, Setx+/- and Setx-/- females produced significantly fewer pups than Setx+/+ females from 7 months of age onwards. These data show that SETX is critical for preventing POA in mice, likely by preserving DNA integrity in oocytes. Intriguingly, heterozygous Setx loss causes an equally severe impact on ovarian ageing as homozygous Setx loss. Because heterozygous SETX disruption is less likely to produce systemic effects, SETX compromise could underpin some cases of insidious POA.

Assessment of premature menopause on the sexual function and quality of life in women.

INTRODUCTION: Premature Ovarian Insufficiency (POI) is characterized by ending menstruation in women under 40 years of age. It has a significant effect on women's sexuality and mental health and quality of life. This study aimed to evaluate the sexual function and quality of life of premature menopausal women. METHODS: This study was a case-control study on 132 people (66 women with a diagnosis of POF and 66 women of reproductive age with normal ovarian function) who were matched in terms of the age, presenting to Women's Clinic in Jahrom in 2019. The WHOQOL-BREF questionnaire and the Female Sexual Function Index (FSFI) questionnaire were used to collect data. p < .05 was considered statistically significant. RESULTS: The mean score of sexual function in premature menopausal women was 21.35 ± 4.82 and in non-menopausal women was 25.4 ± 6.61 (OR = 0.11, 95% CI = 0.04-0.28). All areas of sexual function; desires disorder (OR = 0.21 95% CI = 0.07-0.56), Arousal disorder(OR = 0.28, 95% CI = 0.08-0.93), orgasm disorder (OR = 0.36 95% CI = 0.16-0.80), lubrication disorder (OR = 0.21 95% CI= 0.05-0.78), satisfaction disorder (OR = 0.11, 95% CI = 0.04-0.28) and quality of life domains: physical health (OR = 0.4 95%CI = 0.06-0.3), mental health (OR = 0.28 95% CI = 0.06-0.1), environmental health (OR = 0.22 95%CI = 0.04-0.6) and social health (OR = 0.28 95%CI = 0.01-0.2) saw a decrease in the premature menopausal women group compared to the control group. CONCLUSION: The results demonstrated that premature menopausal women are found to be weaker than the control group in all areas of sexual function and quality of life. Among the areas of sexual function, such as libido, arousal, satisfaction, and pain have the most impact on quality of life. Therefore, based on the results from improving sexual function, this issue can improve the quality of life.

Human umbilical cord mesenchymal stem cells (hUCMSCs) promotes the recovery of ovarian function in a rat model of premature ovarian failure (POF).

AIMS: Our study was to evaluate the benefits of human umbilical cord mesenchymal stem cells (hUCMSCs) for the prevention of premature ovarian failure (POF) in a rat model. MATERIALS AND METHODS: 80 female SD rats aged between 6 and 8 weeks were randomly divided into 4 groups A, B, C and D. Rats in group A is normal control group; group B, C and D received zona pellucida glycoprotein 3 (pZP3) administration to induce POF model. Among these, group B is model control group; group C received PBS injection in ovaries and group D received hUCMSCs injection in ovaries, all injections were performed after modeling on the same day. Estrus cycle; serum hormone level of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and amount of ovarian follicles were detected 20 days after treatment. RESULTS: We successfully injected hUCMSCs in the ovary tissue of a POF rat. The estrus cycle and hormone expression of the rats in group D tends to be normal. Histological studies indicated that hUCMSCs transplantation increased the amount of ovarian follicles. CONCLUSIONS: This study shows that hUCMSCs may have a preventive effect on POF rats.

Live birth after in vitro maturation in women with gonadotropin resistance ovary syndrome: report of two cases.

PURPOSE: Gonadotropin-resistant ovary syndrome (GROS) is a rare endocrine disorder that causes hypergonadotropic hypogonadism, amenorrhea, and infertility. This study reports live birth in two women with GROS who underwent fertility treatment with in vitro maturation (IVM). METHODS: Both patients had primary infertility, amenorrhea (primary and secondary), typical secondary sexual characters, elevated gonadotropin levels, normal ovarian reserve, normal chromosomal characteristics, and previous nonresponsiveness gonadotropin stimulations. One patient had polymorphism of the follicle-stimulating hormone receptor, which is a predictor of poor ovarian response. Given unresponsiveness to exogenous gonadotropin stimulations, IVM with human chorionic gonadotropin priming (hCG-IVM) was performed in both patients. All transferrable embryos were vitrified. RESULTS: Both patients achieved pregnancy after their first frozen embryos transfer, and each delivered a healthy baby boy. CONCLUSIONS: These results suggest that IVM should be a first-line therapeutic option for patients with GROS.

Autoimmunological serum parameters and bone mass density in premature ovarian insufficiency: a retrospective cohort study.

PURPOSE: It is still not clear whether to screen women with primary premature ovarian insufficiency for autoimmunity. Moreover, a possible association of autoimmunity with decreased bone mass density in premature ovarian insufficiency patients has not been evaluated. Thus, the objectives of this study were to review our experience with the use of an autoimmune screening panel in premature ovarian insufficiency women and to focus on bone mass density. METHODS: In a retrospective cohort study, 76 chromosomally normal women with primary premature ovarian insufficiency were included. The main outcome parameters were the results of an autoimmune screening panel and of dual-energy X-ray absorptiometry. RESULTS: Median age was 33 years. Sixty percent of premature ovarian insufficiency patients revealed abnormal dual-energy X-ray absorptiometry results (minimal T-score < -1.0). Any signs of autoimmunity were found in 21 women (36.2%). The most frequent abnormal results were increased thyroperoxidase antibodies (24.1%) and thyroglobulin antibodies (20.7%). A longer duration of amenorrhea (ß = -0.015; p = 0.007), any abnormality during autoimmune screening (ß = -0.940; p = 0.010), and a lower body mass index (ß = -0.057; p = 0.036) were associated with a lower minimal T-score. CONCLUSION: In chromosomally normal women with primary premature ovarian insufficiency, the prevalence of autoimmunity and decreased bone mass density seem high. Our data highlight the association between autoimmune abnormalities and decreased dual-energy X-ray absorptiometry results.

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

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.

Ovarian Aging: Molecular Mechanisms and Medical Management.

This is a short review of the basic molecular mechanisms of ovarian aging, written with a particular focus on the use of this data to improve the diagnostic and therapeutic protocols both for women affected by physiological (age-related) ovarian decay and for those suffering premature ovarian insufficiency. Ovarian aging has a genetic basis that conditions the ovarian activity via a plethora of cell-signaling pathways that control the functions of different types of cells in the ovary. There are various factors that can influence these pathways so as to reduce their efficiency. Oxidative stress, often related to mitochondrial dysfunction, leading to the apoptosis of ovarian cells, can be at the origin of vicious circles in which the primary cause feeds back other abnormalities, resulting in an overall decline in the ovarian activity and in the quantity and quality of oocytes. The correct diagnosis of the molecular mechanisms involved in ovarian aging can serve to design treatment strategies that can slow down ovarian decay and increase the quantity and quality of oocytes that can be obtained for an in vitro fertilization attempt. The available treatment options include the use of antioxidants, melatonin, growth hormones, and mitochondrial therapies. All of these treatments have to be considered in the context of each couple's history and current clinical condition, and a customized (patient-tailored) treatment protocol is to be elaborated.

Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes.

Abnormal trinucleotide expansions cause rare disorders that compromise quality of life and, in some cases, lifespan. In particular, the expansions of the CGG-repeats stretch at the 5'-UTR of the Fragile X Mental Retardation 1 (FMR1) gene have pleiotropic effects that lead to a variety of Fragile X-associated syndromes: the neurodevelopmental Fragile X syndrome (FXS) in children, the late-onset neurodegenerative disorder Fragile X-associated tremor-ataxia syndrome (FXTAS) that mainly affects adult men, the Fragile X-associated primary ovarian insufficiency (FXPOI) in adult women, and a variety of psychiatric and affective disorders that are under the term of Fragile X-associated neuropsychiatric disorders (FXAND). In this review, we will describe the pathological mechanisms of the adult "gain-of-function" syndromes that are mainly caused by the toxic actions of CGG RNA and FMRpolyG peptide. There have been intensive attempts to identify reliable peripheral biomarkers to assess disease progression and onset of specific pathological traits. Mitochondrial dysfunction, altered miRNA expression, endocrine system failure, and impairment of the GABAergic transmission are some of the affectations that are susceptible to be tracked using peripheral blood for monitoring of the motor, cognitive, psychiatric and reproductive impairment of the CGG-expansion carriers. We provided some illustrative examples from our own cohort. Understanding the association between molecular pathogenesis and biomarkers dynamics will improve effective prognosis and clinical management of CGG-expansion carriers.

Exosomes as Biomarkers for Female Reproductive Diseases Diagnosis and Therapy.

Cell-cell communication is an essential mechanism for the maintenance and development of various organs, including the female reproductive system. Today, it is well-known that the function of the female reproductive system and successful pregnancy are related to appropriate follicular growth, oogenesis, implantation, embryo development, and proper fertilization, dependent on the main regulators of cellular crosstalk, exosomes. During exosome synthesis, selective packaging of different factors into these vesicles happens within the originating cells. Therefore, exosomes contain both genetic and proteomic data that could be applied as biomarkers or therapeutic targets in pregnancy-associated disorders or placental functions. In this context, the present review aims to compile information about the potential exosomes with key molecular cargos that are dysregulated in female reproductive diseases which lead to infertility, including polycystic ovary syndrome (PCOS), premature ovarian failure (POF), Asherman syndrome, endometriosis, endometrial cancer, cervical cancer, ovarian cancer, and preeclampsia, as well as signaling pathways related to the regulation of the reproductive system and pregnancy outcome during these pathological conditions. This review might help us realize the etiology of reproductive dysfunction and improve the early diagnosis and treatment of the related complications.

A recurrent missense variant in HARS2 results in variable sensorineural hearing loss in three unrelated families.

HARS2 encodes mitochondrial histidyl-tRNA synthetase (HARS2), which links histidine to its cognate tRNA in the mitochondrial matrix. Biallelic variants in HARS2 are associated with Perrault syndrome, a rare recessive condition characterized by sensorineural hearing loss in both sexes and primary ovarian insufficiency in 46,XX females. Some individuals with Perrault syndrome have a broader phenotypic spectrum with neurological features, including ataxia and peripheral neuropathy. Here, we report a recurrent variant in HARS2 in association with sensorineural hearing loss. In affected individuals from three unrelated families, the variant HARS2 c.1439G>A p.(Arg480His) is present as a heterozygous variant in trans to a putative pathogenic variant. The low prevalence of the allele HARS2 c.1439G>A p.(Arg480His) in the general population and its presence in three families with hearing loss, confirm the pathogenicity of this variant and illustrate the presentation of Perrault syndrome as nonsyndromic hearing loss in males and prepubertal females.

Intra-ovarian injection of platelet-rich plasma into ovarian tissue promoted rejuvenation in the rat model of premature ovarian insufficiency and restored ovulation rate via angiogenesis modulation.

Premature Ovarian Insufficiency (POI) is viewed as a type of infertility in which the menopausal status occurs before the physiological age. Several therapeutic strategies have been introduced in clinic for POI treatment, although the outputs are not fully convincing. Platelet-rich plasma (PRP) is a unique blood product widely applied in regenerative medicine, which is based on the releasing of the growth factors present in platelets α-granules. In the current investigation, we examined the effectiveness of PRP as a therapeutic alternative for POI animals. POI in Wistar albino rats was induced by daily intraperitoneal (IP) administration of gonadotoxic chemical agent, 4-vinylcyclohexene dioxide (VCD) (160 mg/ kg) for 15 consecutive days. After POI induction, the PRP solution was directly injected intra-ovarian in two concentrations via a surgical intervention. Every two weeks post-injection, pathological changes were monitored in the ovaries using Hematoxylin-Eosin staining method, until eight weeks. Follicle Stimulating Hormone (FSH) content in serum was measured, together with the expression of the angiogenic-related transcripts ANGPT2 and KDR by real-time qPCR. Furthermore the fertility status of the treated rats was evaluated by mating trials. Histopathological examination revealed successful POI induction via the depletion of morphologically normal follicles in rats following VCD treatment compared to the control rats. The injection of PRP at two concentrations reduced the number and extent of the follicular atresia and inflammatory responses (p < 0.05). The expression of both ANGPT2 and KDR transcripts were significantly increased in POI rats due to enhanced inflammation, while these values were modulated after PRP administration (p < 0.05) compared to POI rats. FSH showed a decreased trend in concentration eight weeks after PRP treatment, but not statistically significant (p > 0.05). Nevertheless, a clear improvement in litter counts was found in POI rats receiving PRP compared to the non-treated POI group, being able to consider PRP as a facile, quick, accessible, safe and relatively cheap alternative therapeutic strategy to revert POI-related pathologies.

The effect of premature ovarian insufficiency on nasal mucociliary clearance time.

Premature ovarian insufficiency (POI) is a global health concern for women and affects several systems, such as cardiovascular system, autoimmune disease, and psychological status. The aim of this study was to investigate the effect of POI on nasal mucociliary clearance time via saccharin test by comparing postmenopausal women and healthy controls. Thirty-five (35) patients with POI, 35 healthy postmenopausal women and 35 healthy controls were recruited in this study. All study participants underwent measurements of nasal mucociliary clearance time via saccharine test. When women with POI and postmenopausal women compared with the controls, nasal mucociliary clearance time was longer in both women with POI and postmenopausal women. When women with POI were compared with postmenopausal women, the nasal mucociliary clearance time was not difference between two groups. There was a significant prolonged nasal mucociliary clearance time in the women with POI and postmenopausal women. Lower serum estradiol levels in women with POI as well as postmenopausal women had an adverse effect of nasal mucociliary clearance time.

The role of oxidative stress on subclinical atherosclerosis in premature ovarian insufficiency and relationship with carotid intima-media thickness.

Objective: We aimed to investigate the relationship between oxidative stress (OS) and subclinical atherosclerosis in patients with premature ovarian insufficiency (POI), by analyzing the dynamic thiol/disulfide homeostasis (TDH) parameters as an OS marker and carotid intima-media thickness (CIMT).Materials and methods: A total of 69 women, 34 with POI and 35 healthy controls were included in this prospective cross-sectional study. TDH parameters (plasma native thiol, total thiol, disulfide, disulfide/native thiol, native thiol/total thiol, and disulfide/total thiol ratios) and CIMT were measured and compared between the two groups.Results: In primary ovarian insufficiency group, native thiol (p=.009) and total thiol (p=.010) levels were significantly decreased, and CIMT values were significantly increased (p= <.001). CIMT values were negatively correlated with native thiol (r=-0.553, p=.001) and total thiol levels (r=-0.565, p=.001); and positively correlated with age (r = 0.457, p=.007), BMI (r = 0.408, p=.017), and total cholesterol (r = 0.605, p<.001) in POI group.Conclusions: Decreased native thiol and total thiol levels demonstrate the defective anti-oxidant mechanism in POI. Negative correlation between native thiol, total thiol levels, and CIMT means the presence of abnormal anti-oxidant mechanisms may play a role in the development of subclinical atherosclerosis in patients with POI. This is a novel report on the mechanism of subclinical atherosclerosis in women with POI, which needs to be supported with further studies evaluating the pathophysiology of OS.

Novel PMM2 missense mutation in a Chinese family with non-syndromic premature ovarian insufficiency.

PURPOSE: This study sought to identify a disease-related gene in a consanguineous Chinese family in which there were two premature ovarian insufficiency (POI) sisters. METHOD: We used whole-exome sequencing and Sanger sequencing to identify the disease-causing gene. Results were verified using an assay of mutant protein and in silico analyses. RESULT: We identified a novel missense mutation (NM_000303: c.556G>A, p.Gly186Arg) in the PMM2 gene. The two sisters suffer from premature ovarian insufficiency (POI) only and have no other symptoms of congenital disorder of glycosylation type-1a (CDG-Ia). We found that the enzymic activity of the mutant PMM2 protein was reduced by 55.21% (p < 0.05) when compared with wild type, and many in silico tools suggested the mutation is disease-related. CONCLUSION: This particular gene modification results in changes in activity of phosphomannomutase modification, which could lead to PMM2-CDG-Ia with an uncommon phenotype.