Cases Of Primary Ovarian Insufficiency Research Articles

The relationship between primary ovarian insufficiency and gene variations: a prospective case-control study

ABSTRACT Around 70 percent of cases of Primary Ovarian Insufficiency (POI) etiology remain unexplained. The aim of our study is to contribute to the etiology and genetic background of POI. A total of 37 POI patients and 30 women in the reproductive period were included in this prospective, case-control study between August 2020 and December 2021. The women were examined for 36 genes with next-generation sequencing (NGS) panel. Gene variations were detected in 59.5 percent of the patients in the case group. FSHR p.S680N (rs6166, c.2039 G>A) and FSHR p.A307T (rs6165, c.919 G>A) gene variants, which are most frequently located in exon 10 of the FSHR gene, were detected in both groups. Although it was not found that these gene variants were significantly different between the groups, it was also found that they were significantly different in POI patients under 30 years of age and in those with a family history of POI. Variations were detected in 12 genes in POI patients. Two gene variants (FGFR1 [c.386A>C, rs765615419] and KISS1 [c.58 G>A, rs12998]) were detected in both groups, and the remaining gene variants were detected only in POI patients. No differences were detected between the groups in terms of gene variations. However, the gene variations detected only in POI patients may play a role in the etiology of POI.

Family size for women with primary ovarian insufficiency and their relatives.

How does the number of children in women with primary ovarian insufficiency (POI) compare to the number for control women across their reproductive lifespans? Approximately 14% fewer women with POI will have children, but for those able to have children the median number is 1 less than for age-matched controls. Women with POI are often identified when presenting for fertility treatment, but some women with POI already have children and there remains a low chance for pregnancy after the diagnosis. Further, POI is heritable, but it is not known whether relatives of women with POI have a smaller family size than relatives of controls. The study was a retrospective case-control study of women with POI diagnosed from 1995 to 2021 (n = 393) and age-matched controls (n = 393). Women with POI were identified using ICD9 and 10 codes in electronic medical records (1995-2021) from two major healthcare systems in Utah and reviewed for accuracy. Cases were linked to genealogy information in the Utah Population Database. All POI cases (n = 393) were required to have genealogy information available for at least three generations of ancestors. Two sets of female controls were identified: one matched for birthplace (Utah or elsewhere) and 5-year birth cohort, and a second also matched for fertility status (children present). The number of children born and maternal age at each birth were ascertained by birth certificates (available from 1915 to 2020) for probands, controls, and their relatives. The Mann-Whitney U test was used for comparisons. A subset analysis was performed on women with POI and controls who delivered at least one child and on women who reached 45 years to capture reproductive lifespan. Of the 393 women with POI and controls, 211 women with POI (53.7%), and 266 controls (67.7%) had at least one child. There were fewer children born to women with POI versus controls (median (interquartile range) 1 (0-2) versus 2 (0-3); P = 3.33 × 10-6). There were no children born to women with POI and primary amenorrhea or those <25 years old before their diagnosis. When analyzing women with at least one child, women with POI had fewer children compared to controls overall (2 (1-3) versus 2 (2-4); P = 0.017) and when analyzing women who reached 45 years old (2 (1-3) versus 3 (2-4); P = 0.0073). Excluding known donor oocyte pregnancies, 7.1% of women with POI had children born after their diagnosis. There were no differences in the number of children born to relatives of women with POI, including those with familial POI. The data are limited based on inability to determine whether women were trying for pregnancy throughout their reproductive lifespan or were using contraception. Unassisted births after the diagnosis of POI may be slightly over-estimated based on incomplete data regarding use of donor oocytes. The results may not be generalizable to countries or states with late first births or lower birth rates. Approximately half of women with POI will bear children before diagnosis. Although women with POI had fewer children than age matched controls, the difference in number of children is one child per woman. The data suggest that fertility may not be compromised leading up to the diagnosis of POI for women diagnosed at 25 years or later and with secondary amenorrhea. However, the rate of pregnancy after the diagnosis is low and we confirm a birth rate of <10%. The smaller number of children did not extend to relatives when examined as a group, suggesting that it may be difficult to predict POI based on family history. The work in this publication was supported by R56HD090159 and R01HD099487 (C.K.W.). We also acknowledge partial support for the Utah Population Database through grant P30 CA2014 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no conflicts of interest. N/A.

Selected Genetic Factors Associated with Primary Ovarian Insufficiency

Primary ovarian insufficiency (POI) is a heterogeneous disease resulting from non-functional ovaries in women before the age of 40. It is characterized by primary amenorrhea or secondary amenorrhea. As regards its etiology, although many POI cases are idiopathic, menopausal age is a heritable trait and genetic factors play an important role in all POI cases with known causes, accounting for approximately 20% to 25% of cases. This paper reviews the selected genetic causes implicated in POI and examines their pathogenic mechanisms to show the crucial role of genetic effects on POI. The genetic factors that can be found in POI cases include chromosomal abnormalities (e.g., X chromosomal aneuploidies, structural X chromosomal abnormalities, X-autosome translocations, and autosomal variations), single gene mutations (e.g., newborn ovary homeobox gene (NOBOX), folliculogenesis specific bHLH transcription factor (FIGLA), follicle-stimulating hormone receptor (FSHR), forkhead box L2 (FOXL2), bone morphogenetic protein 15 (BMP15), etc., as well as defects in mitochondrial functions and non-coding RNAs (small ncRNAs and long ncRNAs). These findings are beneficial for doctors to diagnose idiopathic POI cases and predict the risk of POI in women.

Spontaneous reports of primary ovarian insufficiency after vaccination: A review of the vaccine adverse event reporting system (VAERS).

Since 2012, reports of primary ovarian insufficiency (POI) temporally associated with receipt of human papillomavirus (HPV) vaccine have been published leading to questions about a potential causal association. A Vaccine Safety Datalink study did not find an increased risk for POI after vaccination. We reviewed the Vaccine Adverse Event Reporting System (VAERS) to describe POI reports. We searched VAERS, a U.S. passive surveillance system, for domestic POI reports received from 01/01/1990 to 12/31/2017 after any vaccination. The search used both Medical Dictionary for Regulatory Activity Preferred Terms and a text-based search for POI and its symptoms. All reports were reviewed, and the American College of Obstetricians and Gynecologists (ACOG) guidelines for POI diagnosis were applied. Data mining for disproportionate reporting was conducted. Six hundred fifty-two reports met the search criteria and clinical review identified 19 POI reports. Most reports (n=16) were received between 2013 and 2017. The median age at vaccination was 14.5years (range 10-25years) and the median interval between first dose of vaccination and reporting the event to VAERS was 43months (range 4-132months; mean 59.6months). Four reports met ACOG diagnostic criteria; one with an underlying cause (47XXX chromosomal abnormality) reported. Eleven reports documented menstrual irregularity≥3months; 5 had≥1 laboratory test result used to diagnose POI. Eighteen of 19 reports described receipt of HPV vaccine with or without other vaccines. Other vaccines reported were meningococcal conjugate vaccine, hepatitis A, varicella and tetanus toxoid, reduced diphtheria toxoid and acellular pertussis. Disproportionate reporting was found for three relevant coding terms after HPV vaccination. POI is rarely reported to VAERS. Most reports contained limited diagnostic information and were submitted after published cases of POI following HPV vaccination. Results of our review do not suggest a safety concern.

Prolidase as a marker of fibrogenesis in idiopathic primary ovarian insufficiency

ObjectivesTo evaluate the serumlevel of prolidase,which isa marker of fibrogenic activity, in women with idiopathic primary ovarian insufficiency (POI). Study DesignThis is a prospective case-control study. Serum prolidase level was compared between the study group including 68 women with POI and control group including 65 normally menstruating women. Serum proline and hydroxyproline levels were also compared. Correlation analyses were performed between the prolidase level and POI related parameters including estradiol (E), follicle stimulating hormone (FSH), anti-mullerian hormone (AMH) levels, and presence of POI family history. ResultsSerum prolidase and proline level were significantly increased in women with the diagnosis of POI compared to the control group (1082.57 (147.53) vs 981.13 (223.26) U/L, 233.30 (83.16) vs 218.94 (82.59) µmol/L, respectively). Prolidase level found to have significant correlations with AMH, E, FSH levels, and presence of POI family history (r = −0.49, p = 0.001; r = −0.39, p = 0.001; r = 0.42, p = 0.001; r = 0.22, p = 0.01; respectively). In receiver operating characteristics analysis, prolidase was shown to be a discriminative factor for POI at 1031.14 U/L cut-off value with 75 % sensitivity and 65 % specificity. Thearea under curve was 0.71 [(95 % CI: 0.62–0.79), p = 0.001]. ConclusionThe current study revealed increased prolidase level in women withPOI. Serum prolidase level was also negatively correlated with the serum AMH level. Considering the present findings,prolidase may be a candidate molecule in assessment of POI cases.

Clinical Approach of Novel Autologous Stem Cell Therapy for Primary Ovarian Insufficiency and Endometrial Regeneration

Bone Marrow-Derived Mesenchymal Stem Cell Fraction (BMSCF) therapy has various applications as potential use in regenerative medicine. Here, we present an original case of Primary ovarian insufficiency associated with poor ovarian reserves and thin endometrium in a woman who achieved a live birth with BMSCF supplemented with PRP (platelet rich plasma). The age between 24 to 42-year-old woman (n=10) came to our centre with primary infertility. Her husband's sperm count and quality was normal

Primary ovarian insufficiency has strong familiality: results of a multigenerational genealogical study

To determine the familiality of primary ovarian insufficiency (POI) at population level through examination of multigenerational genealogical information linked to electronic medical records. Case-control study. Not applicable. Women with POI were identified using International Classification of Disease 9 and 10 codes in electronic medical records (1995-2021) from 2 major health care systems in Utah and reviewed for accuracy. Cases were linked to genealogy information in the Utah Population Database (UPDB). All included POI cases (n = 396) were required to have genealogy information available for at least 3 generations of ancestors. The risk of POI in relatives was compared with population rates for POI matched by age, sex, and birthplace. Not applicable. Relative risk of POI in first-, second-, and third-degree relatives. We identified 396 validated cases of POI with an associated 2,132 first-degree relatives, 5,245 second-degree relatives, and 10,853 third-degree relatives. We found an increased risk of POI among the extended relatives of cases. Specifically, first-degree relatives demonstrated an 18-fold increased risk of POI compared with controls relative risk ([RR],18.52 95% confidence interval [CI], 10.12-31.07), second-degree relatives demonstrated a 4-fold increase (RR, 4.21; CI, 1.15-10.79), and third-degree relatives demonstrated a 2.7-fold increase (RR, 2.65; CI, 1.14-5.21]). This is the first population-based study to assess the familial clustering of POI. The data demonstrate excess familiality, familial clustering of POI in excess compared with matched population rates of disease, among first-, second-, and third-degree relatives. These findings support a genetic contribution to POI.

A truncating variant of RAD51B associated with primary ovarian insufficiency provides insights into its meiotic and somatic functions.

Primary ovarian insufficiency (POI) causes female infertility by abolishing normal ovarian function. Although its genetic etiology has been extensively investigated, most POI cases remain unexplained. Using whole-exome sequencing, we identified a homozygous variant in RAD51B -(c.92delT) in two sisters with POI. In vitro studies revealed that this variant leads to translation reinitiation at methionine 64. Here, we show that this is a pathogenic hypomorphic variant in a mouse model. Rad51bc.92delT/c.92delT mice exhibited meiotic DNA repair defects due to RAD51 and HSF2BP/BMRE1 accumulation in the chromosome axes leading to a reduction in the number of crossovers. Interestingly, the interaction of RAD51B-c.92delT with RAD51C and with its newly identified interactors RAD51 and HELQ was abrogated or diminished. Repair of mitomycin-C-induced chromosomal aberrations was impaired in RAD51B/Rad51b-c.92delT human and mouse somatic cells in vitro and in explanted mouse bone marrow cells. Accordingly, Rad51b-c.92delT variant reduced replication fork progression of patient-derived lymphoblastoid cell lines and pluripotent reprogramming efficiency of primary mouse embryonic fibroblasts. Finally, Rad51bc.92delT/c.92delT mice displayed increased incidence of pituitary gland hyperplasia. These results provide new mechanistic insights into the role of RAD51B not only in meiosis but in the maintenance of somatic genome stability.

Premature menopause and autoimmune primary ovarian insufficiency in two international multi-center cohorts.

ObjectiveTo investigate markers of premature menopause (<40 years) and specifically the prevalence of autoimmune primary ovarian insufficiency (POI) in European women.DesignPostmenopausal women were categorized according to age at menopause and self-reported reason for menopause in a cross-sectional analysis of 6870 women.MethodsVariables associated with the timing of menopause and hormone measurements of 17β-estradiol and follicle-stimulating hormone were explored using multivariable logistic regression analysis. Specific immunoprecipitating assays of steroidogenic autoantibodies against 21-hydroxylase (21-OH), side-chain cleavage enzyme (anti-SCC) and 17alpha-hydroxylase (17 OH), as well as NACHT leucine-rich-repeat protein 5 were used to identify women with likely autoimmune POI.ResultsPremature menopause was identified in 2.8% of women, and these women had higher frequencies of nulliparity (37.4% vs 19.7%), obesity (28.7% vs 21.4%), osteoporosis (17.1% vs 11.6%), hormone replacement therapy (59.1% vs 36.9%) and never smokers (60.1% vs 50.9%) (P < 0.05), compared to women with menopause ≥40 years. Iatrogenic causes were found in 91 (47%) and non-ovarian causes in 27 (14%) women, while 77 (39%) women were classified as POI of unknown cause, resulting in a 1.1% prevalence of idiopathic POI. After adjustments nulliparity was the only variable significantly associated with POI (odds ratio 2.46; 95% CI 1.63–3.42). Based on the presence of autoantibodies against 21 OH and SCC, 4.5% of POI cases were of likely autoimmune origin.ConclusionIdiopathic POI affects 1.1% of all women and almost half of the women with premature menopause. Autoimmunity explains 4.5% of these cases judged by positive steroidogenic autoantibodies.

Modeling primary ovarian insufficiency-associated loci in C. elegans identifies novel pathogenic allele of MSH5.

In women under the age of 40, primary ovarian insufficiency (POI) is a devastating diagnosis with significant prevalence of 1-4% (Rajkovic and Pangas, Semin Reprod Med. 35(3):231-40, 2017). POI is characterized by amenorrhea with elevated levels of follicle stimulating hormone (FSH) and reduced estrogen levels, mimicking the menopausal state. Genetic determinants account for just over 10% of POI cases, yet determining whether particular single nucleotide polymorphisms (SNPs) are pathogenic is challenging. We performed exome sequencing on a cohort of women with POI. CRISPR mutagenesis was employed to create a mutation in a conserved amino acid in the nematode protein. Functional relevance was assessed by analysis of bivalents and aberrant DNA morphologies in diakinesis nuclei. We identified a nonsynonymous c.C1051G; p.R351G variant, in a conserved region of the MSH5 protein. Mutation of this conserved amino acid in the C. elegans homolog, msh-5, revealed defective crossover outcomes in the homozygous and hemizygous states. These studies further implicate MSH5 as a POI gene and c.C1051G; p.R351G variant as likely playing a functional role in mammalian meiosis. This approach also highlights the ability of model organisms, such as C. elegans, to rapidly and inexpensively identify alleles of interest for further studies in mammalian models.

Targeted Next-Generation Sequencing Indicates a Frequent Oligogenic Involvement in Primary Ovarian Insufficiency Onset.

Primary ovarian insufficiency (POI) is one of the major causes of female infertility associated with the premature loss of ovarian function in about 3.7% of women before the age of 40. This disorder is highly heterogeneous and can manifest with a wide range of clinical phenotypes, ranging from ovarian dysgenesis and primary amenorrhea to post-pubertal secondary amenorrhea, with elevated serum gonadotropins and hypoestrogenism. The ovarian defect still remains idiopathic in some cases; however, a strong genetic component has been demonstrated by the next-generation sequencing (NGS) approach of familiar and sporadic POI cases. As recent evidence suggested an oligogenic architecture for POI, we developed a target NGS panel with 295 genes including known candidates and novel genetic determinants potentially involved in POI pathogenesis. Sixty-four patients with early onset POI (range: 10–25 years) of our cohort have been screened with 90% of target coverage at 50×. Here, we report 48 analyzed patients with at least one genetic variant (75%) in the selected candidate genes. In particular, we found the following: 11/64 patients (17%) with two variants, 9/64 (14%) with three variants, 9/64 (14%) with four variants, 3/64 (5%) with five variants, and 2/64 (3%) with six variants. The most severe phenotypes were associated with either the major number of variations or a worse prediction in pathogenicity of variants. Bioinformatic gene ontology analysis identified the following major pathways likely affected by gene variants: 1) cell cycle, meiosis, and DNA repair; 2) extracellular matrix remodeling; 3) reproduction; 4) cell metabolism; 5) cell proliferation; 6) calcium homeostasis; 7) NOTCH signaling; 8) signal transduction; 9) WNT signaling; 10) cell death; and 11) ubiquitin modifications. Consistently, the identified pathways have been described in other studies dissecting the mechanisms of folliculogenesis in animal models of altered fertility. In conclusion, our results contribute to define POI as an oligogenic disease and suggest novel candidates to be investigated in patients with POI.

Primary ovarian insufficiency: a glimpse into the racial and socioeconomic disparities found within third-party reproduction

ObjectiveTo describe a unique case of primary ovarian insufficiency and review the systemic barriers in place that hinder reproductive autonomy for Black women who require third-party reproduction.DesignCase report and review of the literature.SettingSafety-net hospital in an urban community.Patient(s)A 36-year-old Black woman, gravida 0, with primary ovarian insufficiency who desires future fertility but is restricted by systemic barriers.Intervention(s)Chromosome analysis.Main Outcome Measure(s)Not applicable.Result(s)Balanced reciprocal translocation between chromosomes 1 and 13: 46,XX,t(1;13)(q25;q14.1).Conclusion(s)The field of assisted reproductive technology has evolved at an exponential rate, yet it unfortunately benefits some and not all. It is imperative that when we advocate for full spectrum infertility care, that this encompasses everyone. As we continue to further study and develop assisted reproductive technology, we must not forget to consider the factors leading to racial and socioeconomic disparities in reproductive care access, utilization, and outcomes.

WANG Yin¢s experience in treatment of primary ovarian insufficiency

The clinical experience of professor WANG Yin in the treatment of primary ovarian insufficiency are summarized. Regarding acupoints selection, the sancai, named "heaven-earth-human being" method is adopted, focusing on the regulation of the middle jiao and shen (mind/spirit). Regarding needling technique, the elongated needle is used in preference. Besides, the bloodletting and cupping method with filiform-fire needle are innovated to achieve both the reinforcing and the reducing purposes as well as to eliminate stasis. The periodic therapy is applied to comply with the changes in the physiological cycle of gynecology. Acupuncture, Chinese herbal medicine, or the combination of them is selected in consideration of the concrete individual cases of primary ovarian insufficiency.

Status of Estrogen Receptor Beta Gene Polymorphisms rs1256049 and rs4986938 in a cohort of South Indian women with Primary ovarian insufficiency

The current study is aimed to investigate the role of estrogen receptor beta gene polymorphisms for causation of Primary Ovarian insufficiency (POI) in south Indian women. Primary Ovarian insufficiency (POI) is a menstrual disorder presenting with Primary and secondary amenorrhea, decreased estradiol levels and increased gonadotrophin levels. Most cases of POI remain unresolved even after exhaustive investigations and is a significant cause of infertility in women in the reproductive age. In this study a total of 276 subjects, of which 138 POI patients and 138 controls were analysed for biochemical profiles of FSH, LH and Estradiol. Genotypic frequencies were calculated for different models of the SNP rs1256049 and rs4986938 in the Estrogen receptor Beta gene by PCR-RFLP (Restriction length polymorphism) analysis. Statistically, significant relation is found for FSH, LH and Estradiol profiles of a different group of Premature ovarian insufficiency and controls (p&lt;0.0001). Genotypic frequencies between patients and controls were compared, and strength of the interdependence of genotypes and POI is confirmed by the odds ratio and 95% confidence intervals. Incidence of 1082 G&gt;A (rs1256049) polymorphisms and 1730 G&gt;A (rs4986938) were not significantly different in both patient and control group (P=0.21 and P=0.4). The presence of 1082 G&gt;A (rs1256049) polymorphisms and 1730 G&gt;A (rs4986938) is not associated with causation of Premature ovarian insufficiency in south Indian women.

Status of Estrogen Receptor Beta Gene Polymorphisms rs1256049 and rs4986938 in a cohort of South Indian women with Primary ovarian insufficiency

The current study is aimed to investigate the role of estrogen receptor beta gene polymorphisms for causation of Primary Ovarian insufficiency (POI) in south Indian women. Primary Ovarian insufficiency (POI) is a menstrual disorder presenting with Primary and secondary amenorrhea, decreased estradiol levels and increased gonadotrophin levels. Most cases of POI remain unresolved even after exhaustive investigations and is a significant cause of infertility in women in the reproductive age. In this study a total of 276 subjects, of which 138 POI patients and 138 controls were analysed for biochemical profiles of FSH, LH and Estradiol. Genotypic frequencies were calculated for different models of the SNP rs1256049 and rs4986938 in the Estrogen receptor Beta gene by PCR-RFLP (Restriction length polymorphism) analysis. Statistically, significant relation is found for FSH, LH and Estradiol profiles of a different group of Premature ovarian insufficiency and controls (p A (rs1256049) polymorphisms and 1730 G>A (rs4986938) were not significantly different in both patient and control group (P=0.21 and P=0.4). The presence of 1082 G>A (rs1256049) polymorphisms and 1730 G>A (rs4986938) is not associated with causation of Premature ovarian insufficiency in south Indian women.

Urinary cadmium concentrations and risk of primary ovarian insufficiency in women: a case-control study.

Cadmium, a toxic heavy metal that occurs in the environment in large quantities through human activities, has been shown to have adverse effects on female reproductive health. However, the association between cadmium exposure and primary ovarian insufficiency (POI), one of the most prevalent ovarian diseases in women, has not been examined yet. This case-control study involving 169 POI cases and 209 healthy controls was conducted in Zhejiang Province, China. The urinary concentrations of cadmium were determined by inductively coupled plasma mass spectrometry (ICP-MS). In addition, serum levels of reproductive hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Mullerian hormone (AMH) and estradiol, were measured. The median concentration of urinary cadmium in POI cases (0.43μg/L, 0.58μg/g for creatinine adjustment) was significantly higher than that of controls (0.29μg/L, 0.43μg/g for creatinine adjustment). The results of binary logistic regression models showed that the concentrations of urinary cadmium were positively significantly correlated with the odds ratio (ORs) of POI before the adjustment of confounders. After the adjustment, a significantly positive association was still present between the increased concentrations of cadmium and the ORs of POI (2.50, 95% CIs: 1.34-4.65 for the third tertile, p for trend = 0.001). The serum levels of FSH and LH were positively associated with urinary cadmium, while AMH and estradiol levels were inversely correlated. To the best of our knowledge, this is the first reported positive association of cadmium exposure with the risk of POI in women.

Follicle-stimulating hormone receptor autoantibody associated primary ovarian insufficiency successfully treated with corticosteroids: a case report

ObjectiveTo report a case of successful controlled ovarian stimulation (COH) for oocyte cryopreservation in a patient with autoimmune primary ovarian insufficiency (POI) and polyglandular autoimmune syndrome (PGAS) type 2.DesignCase report.SettingPrivate in vitro fertilization clinic.Patient(s)25-Year-old woman, G0, with autoimmune POI and PGAS type 2.Intervention(s)Diagnosis of autoimmune interference with FSH signaling, with subsequent high-dose corticosteroid immune suppression and successful oocyte cryopreservation.Main Outcomes Measure(s)Successful stimulation with exogenous gonadotropins, oocyte retrieval, and cryopreservation.Result(s)Retrieval and cryopreservation of 36 metaphase-II (MII) oocytes.Conclusion(s)Scrutiny of POI cases will facilitate identification of a subset of patients in whom immune suppression with short-term, high-dose corticosteroids may enable successful COH.

A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1.

Primary Ovarian Insufficiency (POI) is a major cause of infertility, but its etiology remains poorly understood. Using whole-exome sequencing in a family with three cases of POI, we identified the candidate missense variant S167L in HSF2BP, an essential meiotic gene. Functional analysis of the HSF2BP-S167L variant in mouse showed that it behaves as a hypomorphic allele compared to a new loss-of-function (knock-out) mouse model. Hsf2bpS167L/S167L females show reduced fertility with smaller litter sizes. To obtain mechanistic insights, we identified C19ORF57/BRME1 as a strong interactor and stabilizer of HSF2BP and showed that the BRME1/HSF2BP protein complex co-immunoprecipitates with BRCA2, RAD51, RPA and PALB2. Meiocytes bearing the HSF2BP-S167L variant showed a strongly decreased staining of both HSF2BP and BRME1 at the recombination nodules and a reduced number of the foci formed by the recombinases RAD51/DMC1, thus leading to a lower frequency of crossovers. Our results provide insights into the molecular mechanism of HSF2BP-S167L in human ovarian insufficiency and sub(in)fertility.

An exome-wide exploration of cases of primary ovarian insufficiency uncovers novel sequence variants and candidate genes.

Primary ovarian insufficiency (POI) implies the cessation of menstruation for several months in women before the age of 40 years and is a major cause of infertility. The study of the contribution of genetic factors to POI has been fueled by the use of whole exome sequencing (WES). Here, to uncover novel causative pathogenic variants and risk alleles, WES has been performed in 12 patients with familial POI (eight unrelated index cases and two pairs of sisters) and six women with early menopause and family history of POI (four index cases and one pair of sisters). Likely causative variants in NR5A1 and MCM9 genes were identified as well as a variant in INHA that requires further investigation. Moreover, we have identified more than one candidate variant in 3 out of 15 familial cases. Taken together, our results highlight the genetic heterogeneity of POI and early menopause and support the hypothesis of an oligogenic inheritance of such conditions, in addition to monogenic inheritance.

Familial primary ovarian insufficiency associated with an SYCE1 point mutation: defective meiosis elucidated in humanized mice.

More than 50% of cases of primary ovarian insufficiency (POI) and nonobstructive azoospermia in humans are classified as idiopathic infertility. Meiotic defects may relate to at least some of these cases. Mutations in genes coding for synaptonemal complex (SC) components have been identified in humans, and hypothesized to be causative for the observed infertile phenotype. Mutation SYCE1 c.721C>T (former c.613C>T)-a familial mutation reported in two sisters with primary amenorrhea-was the first such mutation found in an SC central element component-coding gene. Most fundamental mammalian oogenesis events occur during the embryonic phase, and eventual defects are identified many years later, thus leaving few possibilities to study the condition's etiology and pathogenesis. Aiming to validate an approach to circumvent this difficulty, we have used the CRISPR/Cas9 technology to generate a mouse model with an SYCE1 c.721C>T equivalent genome alteration. We hereby present the characterization of the homozygous mutant mice phenotype, compared to their wild type and heterozygous littermates. Our results strongly support a causative role of this mutation for the POI phenotype in human patients, and the mechanisms involved would relate to defects in homologous chromosome synapsis. No SYCE1 protein was detected in homozygous mutants and Syce1 transcript level was highly diminished, suggesting transcript degradation as the basis of the infertility mechanism. This is the first report on the generation of a humanized mouse model line for the study of an infertility-related human mutation in an SC component-coding gene, thus representing a proof of principle.