scholarly journals Aberrant and constitutive expression of FOXL2 impairs ovarian development and functions in mice

2020 ◽  
Vol 103 (5) ◽  
pp. 966-977
Author(s):  
Barbara Nicol ◽  
Karina Rodriguez ◽  
Humphrey H-C Yao
Keyword(s):  
Ovarian Development ◽  
Constitutive Expression ◽  
Cell Types ◽  
Primary Ovarian Insufficiency ◽  
Fetal Life ◽  
Loss Of Function ◽  
Ovarian Insufficiency ◽  
Ovarian Cell ◽  
Theca Cells ◽  
The Impact

Abstract Development and functions of the ovary rely on appropriate signaling and communication between various ovarian cell types. FOXL2, a transcription factor that plays a key role at different stages of ovarian development, is associated with primary ovarian insufficiency and ovarian cancer as a result of its loss-of-function or mutations. In this study, we investigated the impact of aberrant, constitutive expression of FOXL2 in somatic cells of the ovary. Overexpression of FOXL2 that started during fetal life resulted in defects in nest breakdown and consequent formation of polyovular follicles. Granulosa cell differentiation was impaired and recruitment and differentiation of steroidogenic theca cells was compromised. As a consequence, adult ovaries overexpressing FOXL2 exhibited defects in compartmentalization of granulosa and theca cells, significant decreased steroidogenesis and lack of ovulation. These findings demonstrate that fine-tuned expression of FOXL2 is required for proper folliculogenesis and fertility.

Biallelic loss of function variants in STAG3 result in primary ovarian insufficiency

2021 ◽  
Author(s):  
Leigh A.M. Demain ◽  
Eline Boetje ◽  
Jonathan J. Edgerley ◽  
Emma Miles ◽  
Cheryl T. Fitzgerald ◽  
...  
Keyword(s):  
Primary Ovarian Insufficiency ◽  
Loss Of Function ◽  
Ovarian Insufficiency

scholarly journals OR31-06 Candidate Gene Variants in a Large Cohort of Women with Primary Ovarian Insufficiency

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Bushra Gorsi ◽  
Mika Moriwaki ◽  
Marvin B Moore ◽  
Aleksandar Rajkovic ◽  
Lawrence M Nelson ◽  
...  
Keyword(s):  
Functional Model ◽  
Primary Ovarian Insufficiency ◽  
Composite Likelihood ◽  
Large Cohort ◽  
Gene Variants ◽  
Loss Of Function ◽  
Test Statistic ◽  
Ovarian Insufficiency ◽  
Total N

Abstract Primary ovarian insufficiency (POI) is highly heritable. The majority of cases have no known cause. We hypothesized that mutations in previously identified genes or genes from the same pathways are the cause of POI in a recessive or dominant manner. Subjects included 294 women diagnosed with POI (amenorrhea with an elevated FSH level). All had a 46XX karyotype, and normal FMR1 repeat number. Subjects were recruited in Boston (n=95), at the NIH and Washington University (n=98), and in Pittsburgh (n=98). Controls included subjects recruited for health in old age and disorders unrelated to reproduction or cancer, and subjects from the 1000 Genomes Project (total n=587). Variants were called using the Sentieon software package (https://www.sentieon.com). Case and control samples were stratified on ethnicity, relatedness and heterozygosity. Peddy and XPAT were used to calculate quality control metrics to detect outlier samples for removal from analysis to create a homogenous dataset. The number of cases (227) and controls (458) was adjusted for downstream analysis. XPAT imposed additional quality filters and removed variants. A second filter removed variants that did not pass a Gnomad filter of <0.001 allele frequency. VAAST was used to determine a composite likelihood ratio (CLR) as the test statistic to represent the aggregate burden of variants of affected individuals in each transcript relative to a set of 458 control genomes. The significance of each transcript’s VAAST CLR score was evaluated by 1 million permutations. We screened exomes for variants in previously identified genes causing POI in humans and those demonstrating infertility in a male or female mouse model. We also used the American College of Medical Genetics and Genomics standards for interpretation of pathogenicity of a variant, with priority on null variants in genes with probability of loss of function intolerance based on the observed vs. expected rate in gnomAD, in vivo or in vitro functional evidence of a damaging effect, significantly increased prevalence compared to controls, i.e. not found in any controls or in fewer than 10 in the gnomAD database if the subject had a matching race/ethnicity. Thirty-four subjects were removed for poor quality exomes and relatedness. Fifty-three subjects had at least one variant in a previously identified POI gene or one in which there was a previously identified functional model. Two subjects carried recessive variants and 30 carried at least one novel heterozygous candidate variant for follow up. Analysis of genetic causes of POI in this large cohort identified candidate causal gene variants in over half of the subjects. The data demonstrate that the genetic architecture is heterogeneous. Although recessive mutations have been identified in consanguineous families, the data suggest that a dominant or oligogenic pattern of inheritance may be important.

scholarly journals A critical analysis of the impact of endocrine disruptors as a possible etiology of primary ovarian insufficiency

2020 ◽  
Author(s):  
Cecilia de Souza Monteiro ◽  
Erica Becker de Sousa Xavier ◽  
João Pedro Junqueira Caetano ◽  
Ricardo Mello Marinho
Keyword(s):  
Endocrine Disruptors ◽  
Critical Analysis ◽  
Primary Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
The Impact

scholarly journals Oestrogen receptor α and β, androgen receptor and progesterone receptor mRNA and protein localisation within the developing ovary and in small growing follicles of sheep

Reproduction ◽  
2006 ◽  
Vol 131 (1) ◽  
pp. 81-92 ◽  
Author(s):  
Jennifer L Juengel ◽  
Derek A Heath ◽  
Laurel D Quirke ◽  
Kenneth P McNatty
Keyword(s):  
Granulosa Cells ◽  
Ovarian Development ◽  
Cell Types ◽  
Surface Epithelium ◽  
Fetal Life ◽  
Follicular Growth ◽  
Early Stages ◽  
Thecal Cells ◽  
Protein Localisation ◽  
Type 3

A first step to elucidating the roles that steroids may play in the processes of ovarian development and early follicular growth is to identify the cell types that are likely to be receptive to steroids. Thus, cell types expressing receptors for oestrogen (α and β form; ERα and ERβ respectively), androgen (AR) and progesterone (PR) were determined by in situ hybridisation and immunohistochemistry in ovine ovarian tissues collected during ovarian development and follicular formation (days 26–75 of fetal life) as well as during the early stages of follicular growth. Expression of ERβ was observed early during ovarian development and continued to be expressed throughout follicular formation and also during the early stages of follicular growth. ERβ was identified in germ cells as well as in the granulosa cells. At the large preantral stage of follicular growth, expression of ERα was also consistently observed in granulosa cells. AR was first consistently observed at day 55 of fetal life in stroma cells throughout the ovary. Within the follicle, expression was observed in granulosa and thecal cells from the type-2 to -3 stage of follicular growth. PR mRNA did not appear to be expressed during ovarian development (days 26–75 of gestation). However, PR (mRNA and protein) was observed in the theca of type-3 (small preantral) and larger follicles, with mRNA – but not protein – observed in granulosa cells of some type-4 and 5 follicles. Expression of ERβ, ERα and AR, as well as PR, was also observed in the surface epithelium and ovarian stroma of the fetal, neonatal and adult ovary. Thus, in sheep, steroid hormones have the potential to regulate the function of a number of different ovarian cell types during development, follicular formation and early follicular growth.

Novel NOBOX loss-of-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort

2011 ◽  
Vol 32 (10) ◽  
pp. 1108-1113 ◽  
Author(s):  
Justine Bouilly ◽  
Anne Bachelot ◽  
Isabelle Broutin ◽  
Philippe Touraine ◽  
Nadine Binart
Keyword(s):  
Primary Ovarian Insufficiency ◽  
Loss Of Function ◽  
Ovarian Insufficiency ◽  
Large Primary

Two rare loss-of-function variants in the STAG3 gene leading to primary ovarian insufficiency

2019 ◽  
Vol 62 (3) ◽  
pp. 186-189 ◽  
Author(s):  
Monica M. França ◽  
Mirian Y. Nishi ◽  
Mariana F.A. Funari ◽  
Antonio M. Lerario ◽  
Edmund C. Baracat ◽  
...  
Keyword(s):  
Primary Ovarian Insufficiency ◽  
Loss Of Function ◽  
Ovarian Insufficiency

BMPR1A and BMPR1B Missense Mutations Cause Primary Ovarian Insufficiency

2019 ◽  
Vol 105 (4) ◽  
pp. e1449-e1457 ◽  
Author(s):  
Lucie Renault ◽  
Liliana C Patiño ◽  
Françoise Magnin ◽  
Brigitte Delemer ◽  
Jacques Young ◽  
...  
Keyword(s):  
Ovarian Function ◽  
Chromosomal Abnormalities ◽  
Primary Ovarian Insufficiency ◽  
Bone Morphogenic Protein ◽  
Bmp Signaling ◽  
Pathophysiological Mechanism ◽  
Missense Mutations ◽  
Ovarian Insufficiency ◽  
The Impact

Abstract Context Primary ovarian insufficiency (POI) is a frequently occurring disorder affecting approximately 1% of women under 40 years of age. POI, which is characterized by the premature depletion of ovarian follicles and elevated plasma levels of follicle-stimulating hormone, leads to infertility. Although various etiological factors have been described, including chromosomal abnormalities and gene mutations, most cases remain idiopathic. Objective To identify and to functionally validate new sequence variants in 2 genes that play a key role in mammalian ovarian function, BMPR1A and BMPR1B (encoding for bone morphogenic protein receptor), leading to POI. Methods The impact on bone morphogenic protein (BMP) signaling of BMPR1A and BMPR1B variants, previously identified by whole-exome sequencing on 69 women affected by isolated POI, was established by different in vitro functional experiments. Results We demonstrate that the BMPR1A-p.Arg442His and BMPR1B-p.Phe272Leu variants are correctly expressed and located but lead to an impairment of downstream BMP signaling. Conclusion In accordance with infertility observed in mice lacking Bmpr1a in the ovaries and in Bmpr1b-/- mice, our results unveil, for the first time, a link between BMPR1A and BMPR1B variants and the origin of POI. We show that BMP signaling impairment through specific BMPR1A and BMPR1B variants is a novel pathophysiological mechanism involved in human POI. We consider that BMPR1A and BMPR1B variants constitute genetic biomarkers of the origin of POI and have clinical utility.

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

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Natalia Felipe-Medina ◽  
Sandrine Caburet ◽  
Fernando Sánchez-Sáez ◽  
Yazmine B Condezo ◽  
Dirk G de Rooij ◽  
...  
Keyword(s):  
Missense Variant ◽  
Primary Ovarian Insufficiency ◽  
Loss Of Function ◽  
Ovarian Insufficiency ◽  
Knock Out ◽  
Recombination Nodules ◽  
Hypomorphic Allele ◽  
Whole Exome ◽  
Gene Functional Analysis ◽  
Knock Out Mouse

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.

scholarly journals A Long contiguous stretches of homozygosity disclosed a novel biallelic pathogenic variant in STAG3 causing Primary Ovarian Insufficiency

2021 ◽  
Author(s):  
Simona Mellone ◽  
Marco Zavattaro ◽  
Denise Vurchio ◽  
Sara Ronzani ◽  
Marina Caputo ◽  
...  
Keyword(s):  
Genetic Defect ◽  
Specific Protein ◽  
Primary Ovarian Insufficiency ◽  
Snp Analysis ◽  
Loss Of Function ◽  
Degree Relative ◽  
Genetic Etiology ◽  
Ovarian Insufficiency ◽  
Pathogenic Variants ◽  
Germ Cell Differentiation

Abstract Background: Primary ovarian insufficiency (POI) refers to an etiologically heterogeneous disorder characterized by hypergonadotropic hypogonadism that represents a major cause of infertility in women under 40 years. Most cases of isolated POI still appear sporadically, but ∼10–15% have an affected first-degree relative, indicating a significant genetic etiology. Several genes implicated in development, meiosis, hormonal signaling and metabolism are involved in the genetic form of the disorder in both syndromic and isolated POI. However, most cases of POI remain unsolved even after exhaustive investigation. Results: Here is reported a 19-year-old Senegalese female affected by non-syndromic POI showing primary amenorrhoea, who well answered to the hormonal induction of puberty reaching a complete sexual maturation in two years. In order to investigate the presence of a genetic defect, aCGH-SNP analysis was performed. A 13.5 Mb long contiguous stretch of homozygosity (LCSH) region on chromosome 7q21.13-q22.1 was identified where the exome sequencing revealed a novel homozygous 4-bp deletion (c.3381_3384delAGAA) in STAG3 . Pathogenic variants in this gene, encoding for a meiosis-specific protein, have been previously reported as cause POI in only seven families and recently as cause of infertility in a male. The here identified mutation leads to the truncation of the last 55 aminoacids, confirming the important role in meiosis of the STAG3 C-terminal domain. Conclusions: In conclusion we identified a loss of function variant in STAG3 in a Senegalese woman with POI reinforcing the role the cohesin complex in the genetic etiology of this disorder. This gene should be included in the screening of POI to offer a better genetic counseling and long term follow-up considering the risk of ovarian tumor in woman carrying pathogenic variants in genes involved in germ cell differentiation.

scholarly journals ZSWIM7 Is Associated With Human Female Meiosis and Familial Primary Ovarian Insufficiency

2021 ◽  
Author(s):  
Sinéad M McGlacken-Byrne ◽  
Polona Le Quesne Stabej ◽  
Ignacio Del Valle ◽  
Louise Ocaka ◽  
Andrey Gagunashvili ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Rna Sequencing ◽  
Gonad Development ◽  
Recessive Model ◽  
Primary Ovarian Insufficiency ◽  
Ovary Development ◽  
Loss Of Function ◽  
Ovarian Insufficiency ◽  
Qrt Pcr ◽  
Fetal Ovary

Abstract Background Primary ovarian insufficiency (POI) affects 1% of women and is associated with significant medical consequences. A genetic cause for POI can be found in up to 30% of women, elucidating key roles for these genes in human ovary development. Objective We aimed to identify the genetic mechanism underlying early-onset POI in 2 sisters from a consanguineous pedigree. Methods Genome sequencing and variant filtering using an autosomal recessive model was performed in the 2 affected sisters and their unaffected family members. Quantitative reverse transcriptase PCR (qRT-PCR) and RNA sequencing were used to study the expression of key genes at critical stages of human fetal gonad development (Carnegie Stage 22/23, 9 weeks post conception (wpc), 11 wpc, 15/16 wpc, 19/20 wpc) and in adult tissue. Results Only 1 homozygous variant cosegregating with the POI phenotype was found: a single nucleotide substitution in zinc finger SWIM-type containing 7 (ZSWIM7), NM_001042697.2: c.173C > G; resulting in predicted loss-of-function p.(Ser58*). qRT-PCR demonstrated higher expression of ZSWIM7 in the 15/16 wpc ovary compared with testis, corresponding to peak meiosis in the fetal ovary. RNA sequencing of fetal gonad samples showed that ZSWIM7 has a similar temporal expression profile in the developing ovary to other homologous recombination genes. Main conclusions Disruption of ZSWIM7 is associated with POI in humans. ZSWIM7 is likely to be important for human homologous recombination; these findings expand the range of genes associated with POI in women.

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