Genetics of primary ovarian insufficiency: new developments and opportunities

BACKGROUND Primary ovarian insufficiency (POI) is characterized by marked heterogeneity, but with a significant genetic contribution. Identifying exact causative genes has been challenging, with many discoveries not replicated. It is timely to take stock of the field, outlining the progress made, framing the controversies and anticipating future directions in elucidating the genetics of POI. METHODS A search for original articles published up to May 2015 was performed using PubMed and Google Scholar, identifying studies on the genetic etiology of POI. Studies were included if chromosomal analysis, candidate gene screening and a genome-wide study were conducted. articles identified were restricted to English language full-text papers. RESULTS Chromosomal abnormalities have long been recognized as a frequent cause of POI, with a currently estimated prevalence of 10?13%. Using the traditional karyotype methodology, monosomy X, mosaicism, X chromosome deletions and rearrangements, X-autosome translocations, and isochromosomes have been detected. Based on candidate gene studies, single gene perturbations unequivocally having a deleterious effect in at least one population include Bone morphogenetic protein 15 (BMP15), Progesterone receptor membrane component 1 (PGRMC1), and Fragile X mental retardation 1 (FMR1) premutation on the X chromosome; Growth differentiation factor 9 (GDF9), Folliculogenesis specific bHLH transcription factor (FIGLA), Newborn ovary homeobox gene (NOBOX), Nuclear receptor subfamily 5, group A, member 1 (NR5A1) and Nanos homolog 3 (NANOS3) seem likely as well, but mostly being found in no more than 1?2% of a single population studied. Whole genome approaches have utilized genome-wide association studies (GWAS) to reveal loci not predicted on the basis of a candidate gene, but it remains difficult to locate causative genes and susceptible loci were not always replicated. Cytogenomic methods (array CGH) have identified other regions of interest but studies have not shown consistent results, the resolution of arrays has varied and replication is uncommon. Whole-exome sequencing in non-syndromic POI kindreds has only recently begun, revealing mutations in the Stromal antigen 3 (STAG3), Synaptonemal complex central element 1 (SYCE1), minichromosome maintenance complex component 8 and 9 (MCM8, MCM9) and ATP-dependent DNA helicase homolog (HFM1) genes. Given the slow progress in candidate-gene analysis and relatively small sample sizes available for GWAS, family-based whole exome and whole genome sequencing appear to be the most promising approaches for detecting potential genes responsible for POI. CONCLUSION Taken together, the cytogenetic, cytogenomic (array CGH) and exome sequencing approaches have revealed a genetic causation in ?20?25% of POI cases. Uncovering the remainder of the causative genes will be facilitated not only by whole genome approaches involving larger cohorts in multiple populations but also incorporating environmental exposures and exploring signaling pathways in intragenic and intergenic regions that point to perturbations in regulatory genes and networks

Novel NR5A1 Missense Mutation in Premature Ovarian Failure: Detection in Han Chinese Indicates Causation in Different Ethnic Groups

Background The etiology of most premature ovarian failure (POF) cases is usually elusive. Although genetic causes clearly exist and a likely susceptible region of 8q22.3 has been discovered, no predominant explanation exists for POF. More recently, evidences have indicated that mutations in NR5A1 gene could be causative for POF. We therefore screened for mutations in the NR5A1 gene in a large cohort of Chinese women with non-syndromic POF. Methods Mutation screening of NR5A1 gene was performed in 400 Han Chinese women with well-defined 46,XX idiopathic non-syndromic POF and 400 controls. Subsequently, functional characterization of the novel mutation identified was evaluated in vitro. Results A novel heterozygous missense mutation [c.13T\u3eG (p.Tyr5Asp)] in NR5A1 was identified in 1 of 384 patients (0.26%). This mutation impaired transcriptional activation on Amh, Inhibin-a, Cyp11a1and Cyp19a1 gene, as shown by transactivation assays. However, no dominant negative effect was observed, nor was there impact on protein expression and nuclear localization. Conclusions This novel mutation p.Tyr5Asp, in a novel non-domain region, is presumed to result in haploinsufficiency. Irrespectively, perturbation in NR5A1 is not a common explanation for POF in Chinese

Anisometropia is independently associated with both spherical and cylindrical ametropia

Purpose. To explore the associations between anisometropia and spherical ametropia, astigmatism, age, and sex. Method. Associations between the prevalence and magnitude of anisometropia with age, sex, spherical power, and cylindrical power, were assessed in a group of 90,884 subjects attending optometry practices in the United Kingdom. Logistic regression models were used to assess the independent contribution of each explanatory variable. Results. Logistic regression analyses that included all subjects or just those aged 20 to 40 years showed that spherical ametropia and astigmatism were independently associated with anisometropia (myopes, P < 1.0E–61; hyperopes, P < 1.0E–11). Anisometropia was relatively stable between the ages of 20 and 40 years, but then became more common with age, in myopes from the age of 40 years onward (P < 0.003) and in hyperopes from the age of 70 years onward (P < 1.0E–6). Sex was not associated with anisometropia to a clinically significant extent. Conclusions. This is the first study to show an independent association between anisometropia and both spherical ametropia and astigmatism. The results also suggest that the previously noted increased prevalence of anisometropia with age occurs later in hyperopes than in myopes, once other covariates have been controlled for. However, it could not be ruled out that this latter effect was due to clinical selection bias in our sample. The findings suggest that research projects involving the recruitment of highly ametropic subjects, such as those investigating the genetics of refractive error, may benefit by avoiding the use of stringent inclusion criteria for anisometropia, because otherwise a large proportion of the relevant population will be excluded

Proteomic analysis of sex conversion induced by CPPU in male grapevine of Vitis amurensis

If N-(2-chloro-4-pyridyl)-N′-phenylurea (CPPU) could induce sex conversion in male plants of Vitis amurensis Rupr., this would reduce blindness of selection for male parents according to the fruit characters in cold-tolerant and disease-tolerant grape crossbreeding. Flower bud samples of male plants were treated with 100 mg∙L-1 CPPU at 15 days before anthesis. Two-dimensional gel electrophoresis (2-DE) was used to analyze the proteins related to sex conversion at different development time points. More than 600 protein spots were detected. Among them, 31 differentially expressed proteins were identified by MALDI-TOF/TOF, and 24 protein spots could be assigned to a probable function. Seventeen proteins participated in the sex conversion and with complex interaction. Sex conversion might receive the ROS signal in the beginning, and then pollen tube proteins were proposed to down-regulate to repress the stamen development, while the up-regulated cell elongation protein might promote the development of pistil. Adenine phosphoribosyl transferase 3 was proposed as the key protein in the sex organ conversion that was up-regulated by CPPU in the male V. amurensis achieving the ability to fruit in the end.

Electrocatalytic CO2 reduction to alcohols by modulating the molecular geometry and Cu coordination in bicentric copper complexes

Published online: 31 August 2022Electrocatalytic reduction of CO2 into alcohols of high economic value offers a promising route to realize resourceful CO2 utilization. In this study, we choose three model bicentric copper complexes based on the expanded and fluorinated porphyrin structure, but different spatial and coordination geometry, to unravel their structure-property-performance correlation in catalyzing electrochemical CO2 reduction reactions.We show that the complexes with higher intramolecular tension and coordination asymmetry manifests a lower electrochemical stability and thus more active Cu centers, which can be reduced during electrolysis to form Cu clusters accompanied by partially-reduced or fragmented ligands. We demonstrate the hybrid structure of Cu cluster and partially reduced O-containing hexaphyrin ligand is highly potent in converting CO2 into alcohols, up to 32.5% ethanol and 18.3% n-propanol in Faradaic efficiencies that have been rarely reported. More importantly, we uncover an interplay between the inorganic and organic phases to synergistically produce alcohols, of which the intermediates are stabilized by a confined space to afford extra O-Cu bonding. This study underlines the exploitation of structure-dependent electrochemical property to steer the CO2 reduction pathway, as well as a potential generic tactic to target alcohol synthesis by constructing organic/inorganic Cu hybrids.Baiyu Yang, Ling Chen, Songlin Xue, Hao Sun, Kun Feng, Yufeng Chen, Xiang Zhang, Long Xiao, Yongze Qin, Jun Zhong, Zhao Deng, Yan Jiao, Yang Pen

The E-cadherin repressor slug and progression of human extrahepatic hilar cholangiocarcinoma

<p>Abstract</p> <p>Objectives</p> <p>This study explored the expression and function of Slug in human extrahepatic hilar cholangiocarcinoma (EHC) to identify its role in tumor progression.</p> <p>Methods</p> <p>The expression of Snail and Slug mRNA in 52 human tissue samples of EHC was investigated. The mRNA of Snail and Slug were quantified using reverse transcriptase-PCR, and correlations with E-cadherin expression and clinicopathological factors were investigated. We then investigated transfection of Slug cDNA in endogenous E-cadherin-positive human EHC FRH0201 cells, selectively induced the loss of E-cadherin protein expression, and then small interfering RNA (siRNA) for inhibition of Slug expression in endogenous Slug-positive human EHC QBC939 cells, selectively induced the loss of Slug protein expression. A Boyden chamber transwell assay was used for invasion.</p> <p>Results</p> <p>Slug mRNA was overexpressed in 18 cases (34.6%) of EHC compared with adjacent noncancerous tissue. E-Cadherin protein expression determined in the same 52 cases by immunohistochemistry was significantly down-regulated in those cases with Slug mRNA overexpression (P = 0.0001). The tumor and nontumor ratio of Slug mRNA was correlated with nodal metastasis(p = 0.0102), distant metastasis (p = 0.0001)and Survival time(p = 0.0443). However, Snail mRNA correlated with neither E-cadherin expression nor tumor invasiveness. By inhibiting Slug expression by RNA interference, we found that reduced Slug levels upregulated E-cadherin and decreased invasion in QBC939 cell. When the QBC939 cells was infected with Slug cDNA,, significant E-cadherin was downregulated and increased invasion in QBC939 cell.</p> <p>Conclusions</p> <p>The results suggested that Slug expression plays an important role in both the regulation of E-cadherin expression and in the acquisition of invasive potential in human EHC. Slug is possibly a potential target for an antitumor therapy blocking the functions of invasion and metastasis in human EHCs.</p

Search for the Lepton Flavor Violation Process J/ψ→eμJ/\psi \to e\mu at BESIII

We search for the lepton-flavor-violating decay of the $J/\psi$ into an electron and a muon using $(225.3\pm2.8)\times 10^{6}$ $J/\psi$ events collected with the BESIII detector at the BEPCII collider. Four candidate events are found in the signal region, consistent with background expectations. An upper limit on the branching fraction of $\mathcal{B}(J/\psi \to e\mu)< 1.5 \times 10^{-7}$ (90% C.L.) is obtained

Search for Baryonic Decays of \psi(3770) and \psi(4040)

By analyzing data samples of 2.9 fb^{-1} collected at \sqrt s=3.773 GeV, 482 pb^{-1} collected at \sqrt s=4.009 GeV and 67 pb^{-1} collected at \sqrt s=3.542, 3.554, 3.561, 3.600 and 3.650 GeV with the BESIII detector at the BEPCII storage ring, we search for \psi(3770) and \psi(4040) decay to baryonic final states, including \Lambda\bar\Lambda\pi^+\pi^-, \Lambda \bar\Lambda\pi^0, \Lambda\bar\Lambda\eta, \Sigma^+ \bar\Sigma^-, \Sigma^0 \bar\Sigma^0, \Xi^-\bar\Xi^+ and \Xi^0\bar\Xi^0 decays. None are observed, and upper limits are set at the 90% confidence level.Comment: 9 pages, 3 figure

Search for the radiative transitions ψ(3770)→γηc\psi(3770)\to\gamma\eta_c and γηc(2S)\gamma\eta_c(2S)

By using a 2.92 fb$^{-1}$ data sample taken at $\sqrt{s} = 3.773$ GeV with the BESIII detector operating at the BEPCII collider, we search for the radiative transitions $\psi(3770)\to\gamma\eta_c$ and $\gamma\eta_c(2S)$ through the hadronic decays $\eta_c(\eta_c(2S))\to K^0_SK^\pm\pi^\mp$. No significant excess of signal events above background is observed. We set upper limits at a 90% confidence level for the product branching fractions to be $\mathcal{B}(\psi(3770)\to\gamma\eta_c)\times \mathcal{B}(\eta_c\to K^0_SK^\pm\pi^\mp) < 1.6\times10^{-5}$ and $\mathcal{B}(\psi(3770)\to\gamma\eta_c(2S))\times \mathcal{B}(\eta_c(2S)\to K^0_SK^\pm\pi^\mp) < 5.6\times10^{-6}$. Combining our result with world-average values of $\mathcal{B}(\eta_c(\eta_c(2S))\to K^0_SK^\pm\pi^\mp)$, we find the branching fractions $\mathcal{B}(\psi(3770)\to\gamma\eta_c) < 6.8\times10^{-4}$ and $\mathcal{B}(\psi(3770)\to\gamma\eta_c(2S)) < 2.0\times10^{-3}$ at a 90% confidence level.Comment: 10 pages, 4 figure