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The Journal of International Medical... May 2021germline variants of the casein kinase 2α subunit (CK2α) gene () have been reported in individuals with the congenital neuropsychiatric disorder Okur-Chung...
Identification of novel variants and the genotype-phenotype relationship in patients with Okur-Chung neurodevelopmental syndrome: a case report and systematic literature review.
germline variants of the casein kinase 2α subunit (CK2α) gene () have been reported in individuals with the congenital neuropsychiatric disorder Okur-Chung neurodevelopmental syndrome (OCNS). Here, we report on two unrelated children with OCNS and review the literature to explore the genotype-phenotype relationship in OCNS. Both children showed facial dysmorphism, growth retardation, and neuropsychiatric disorders. Using whole-exome sequencing, we identified two novel variants: c.479A>G p.(H160R) and c.238C>T p.(R80C). A search of the literature identified 12 studies that provided information on 35 variants in various protein-coding regions of CK2α. By quantitatively analyzing data related to these variants and their corresponding phenotypes, we showed for the first time that mutations in protein-coding CK2α regions appear to influence the phenotypic spectrum of OCNS. Mutations altering the ATP/GTP-binding loop were more likely to cause the widest range of phenotypes. Therefore, any assessment of clinical spectra for this disorder should be extremely thorough. This study not only expands the mutational spectrum of OCNS, but also provides a comprehensive overview to improve our understanding of the genotype-phenotype relationship in OCNS.
Topics: Casein Kinase II; Child; Genotype; Humans; Intellectual Disability; Mutation; Neurodevelopmental Disorders; Phenotype
PubMed: 34038195
DOI: 10.1177/03000605211017063 -
Orphanet Journal of Rare Diseases May 2021Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium... (Review)
Review
BACKGROUND
Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel.
MAIN BODY
A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro.
CONCLUSION
Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.
Topics: Calcium; Calcium Channels, L-Type; Channelopathies; Child; DNA Copy Number Variations; Developmental Disabilities; Humans; Intellectual Disability
PubMed: 33985586
DOI: 10.1186/s13023-021-01850-0 -
Medicine Feb 2021Genetic polymorphisms in the 15q25 region have been associated with the risk of lung cancer (LC). However, studies have yielded conflicting results. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Genetic polymorphisms in the 15q25 region have been associated with the risk of lung cancer (LC). However, studies have yielded conflicting results.
METHODS
Searches were conducted in databases, including PubMed, EMbase, Web of Science, CNKI, and Wanfang, for case-control studies up to August 1, 2019. After retrieving eligible studies and data extraction, we calculated pooled odds ratios with 95% confidence intervals. In the meta-analysis, we included 32 publications with a total of 52,795 patients with LC and 97,493 control cases to evaluate the polymorphisms in the CHRNA5/A3/B4 gene cluster in the 15q25 region.
RESULTS
Data of the meta-analysis showed a significantly increased risk of LC in the presence of genetic polymorphisms (rs1051730, rs16969968, rs8034191). In the smoking subgroup, the CHRNA3 rs1051730 polymorphism was found to contribute to LC risk using following 5 models: the allelic model, the homozygous model, the heterozygous model, the dominant model, and the recessive model. Thus, the rs1051730 polymorphism may modify LC susceptibility under the condition of smoking. Stratification studies for CHRNA5-rs8034191 showed that Caucasian groups with the wild-type genotype (C/C) may be susceptible to LC in all 5 models. No significant relationship between CHRNA3 rs6495309 or rs3743073 and LC susceptibility was found. However, Asians with the rs3743037 B-allele showed an obviously higher risk of LC susceptibility than the Caucasian population, observed via allelic, heterozygous, and dominant models.
CONCLUSIONS
The 3 polymorphisms of rs1051730, rs16969968 and rs8034191 in the CHRNA5/A3/B4 gene cluster in the 15q25 region were associated with LC risk, which might be influenced by ethnicity and smoking status.
Topics: Genetic Predisposition to Disease; Humans; Lung Neoplasms; Multigene Family; Nerve Tissue Proteins; Polymorphism, Single Nucleotide; Receptors, Nicotinic; Risk Factors
PubMed: 33578531
DOI: 10.1097/MD.0000000000024355 -
Scandinavian Journal of Immunology May 2021Complex interactions between the environment and the mucosal immune system underlie inflammatory bowel disease (IBD). The involved cytokine signalling pathways are...
BACKGROUND
Complex interactions between the environment and the mucosal immune system underlie inflammatory bowel disease (IBD). The involved cytokine signalling pathways are modulated by a number of transcription factors, one of which is runt-related transcription factor 3 (RUNX3).
OBJECTIVE
To systematically review the immune roles of RUNX3 in immune regulation, with a focus on the context of IBD.
METHODS
Relevant articles and reviews were identified through a Scopus search in April 2020. Information was categorized by immune cell types, analysed and synthesized. IBD transcriptome data sets and FANTOM5 regulatory networks were processed in order to complement the literature review.
RESULTS
The available evidence on the immune roles of RUNX3 allowed for its description in twelve cell types: intraepithelial lymphocyte, Th1, Th2, Th17, Treg, double-positive T, cytotoxic T, B, dendritic, innate lymphoid, natural killer and macrophages. In the gut, the activity of RUNX3 is multifaceted and context-dependent: it may promote homeostasis or exacerbated reactions via cytokine signalling and regulation of receptor expression. RUNX3 is mostly engaged in pathways involving ThPOK, T-bet, IFN-γ, TGF-β/IL-2Rβ, GATA/CBF-β, SMAD/p300 and a number of miRNAs. RUNX3 targets relevant to IBD may include RAG1, OSM and IL-17B. Moreover, in IBD RUNX3 expression correlates positively with GZMM, and negatively with IFNAR1, whereas in controls, it strongly associates with TGFBR3.
CONCLUSIONS
Dysregulation of RUNX3, mostly in the form of deficiency, likely contributes to IBD pathogenesis. More clinical research is needed to examine RUNX3 in IBD.
Topics: B-Lymphocytes; Core Binding Factor Alpha 3 Subunit; Dendritic Cells; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Intraepithelial Lymphocytes; T-Lymphocytes
PubMed: 33528856
DOI: 10.1111/sji.13025 -
Frontiers in Aging Neuroscience 2020Sarcopenia is an aging process with a decline of skeletal muscle mass and function, which is a challenging public health problem with reduced quality of life in...
Sarcopenia is an aging process with a decline of skeletal muscle mass and function, which is a challenging public health problem with reduced quality of life in patients. The endplate, the post-synaptic part of the neuromuscular junction (NMJ), occupies 0.1% of the myofiber surface area only, but is composed of millions of acetylcholine receptors (AChRs) that are efficient in binding to acetylcholine (ACh) and triggering skeletal muscle contraction. This systematic review aims to examine aging-associated alterations of post-synaptic AChRs, including morphology, function and related gene expression. A systematic literature search was conducted in PubMed, Embase and Web of Science with relevant keywords by two independent reviewers. Original pre-clinical and clinical studies regarding AChRs changes during aging with available full text and written in English were included. Information was extracted from the included studies for further review. In total, 30 articles were included. Various parameters assessing AChRs alterations by radioassay, immunofluorescence, electrophysiology and mechanical test were reported. Endplate fragmentation and denervation were common in old skeletal muscles during aging. To ensure efficient NMJ transmission and force generation, type I or IIb muscle fibers tended to have increased ACh quanta releasing after electrical stimulations, while type IIa muscle fibers tended to have stronger binding between ACh and AChRs, but the overall function of AChRs was reduced during aging. Alterations of AChRs area depended on muscle type, species and the progress of muscle atrophy and type I muscles fibers tended to demonstrate enlarging AChRs areas. Myogenic regulator factors (MRFs) can regulate the expression of AChRs subunits, while decreased MRF4 may lead to expression changes of AChRs subunits during aging. Sarcoglycan-α can delay low-density lipoprotein receptor-related protein 4 (LRP4) degradation. This protein was increased in old muscles but still cannot suppress the degradation of LRP4. Investigating the role of these AChRs-related genes in the process of aging may provide a potential target to treat sarcopenia.
PubMed: 33362532
DOI: 10.3389/fnagi.2020.597811 -
The Indian Journal of Medical ResearchThe COVID-19 pandemic has emerged as a global public health crisis and research groups worldwide are engaged in developing vaccine candidates to curb its transmission,... (Review)
Review
BACKGROUND & OBJECTIVES
The COVID-19 pandemic has emerged as a global public health crisis and research groups worldwide are engaged in developing vaccine candidates to curb its transmission, with a few vaccines having progressed to advanced stages of clinical trials. The aim of this systematic review was to compare immunogenicity and protective efficacy of various SARS-CoV-2 vaccine candidates tested in non-human primate (NHP) models.
METHODS
Literature on effect of SARS-CoV-2 vaccines in NHP models reported on PubMed and preprint platforms (medRxiv and bioRxiv) till October 22, 2020, was searched with the following terms: coronavirus vaccine, COVID-19 vaccine, SARS-CoV-2 vaccine, nonhuman primate, and rhesus macaque.
RESULTS
Our search yielded 19 studies, which reported immune response elicited by 18 vaccine candidates in NHP. All the vaccines induced detectable neutralizing antibody (NAb) titres in the serum of vaccinated animals, with some showing effective viral clearance from various organs. The vaccinated animals also showed nil to mild histopathological changes in their lungs compared to placebo groups in the trials that performed necropsy.
INTERPRETATION & CONCLUSIONS
Our findings highlighted onset of quick immunogenicity and protective efficacy of mRNA-1273, followed by Ad26.CoV2.S, NVX-CoV2373, BNT162b2, RBD and BBV152 vaccine candidates in preclinical trials as compared to the others. NHP data also showed correlation with clinical trial data available for a few vaccines. Preclinical trials of COVID-19 vaccine candidates in NHPs yielded promising results, with some candidates faring better than others.
Topics: 2019-nCoV Vaccine mRNA-1273; Ad26COVS1; Animals; Antibodies, Neutralizing; Antibodies, Viral; BNT162 Vaccine; COVID-19; COVID-19 Vaccines; Disease Models, Animal; Immunogenicity, Vaccine; Macaca mulatta; Primates
PubMed: 33361645
DOI: 10.4103/ijmr.IJMR_4431_20 -
Signal Transduction and Targeted Therapy Oct 2020Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging virus that is highly pathogenic and has caused the recent worldwide pandemic officially named...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging virus that is highly pathogenic and has caused the recent worldwide pandemic officially named coronavirus disease (COVID-19). Currently, considerable efforts have been put into developing effective and safe drugs and vaccines against SARS-CoV-2. Vaccines, such as inactivated vaccines, nucleic acid-based vaccines, and vector vaccines, have already entered clinical trials. In this review, we provide an overview of the experimental and clinical data obtained from recent SARS-CoV-2 vaccines trials, and highlight certain potential safety issues that require consideration when developing vaccines. Furthermore, we summarize several strategies utilized in the development of vaccines against other infectious viruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), with the aim of aiding in the design of effective therapeutic approaches against SARS-CoV-2.
Topics: Angiotensin-Converting Enzyme 2; Antibodies, Viral; Betacoronavirus; COVID-19; COVID-19 Vaccines; Clinical Trials as Topic; Coronavirus Infections; Gene Expression Regulation; Humans; Immunity, Innate; Immunization Schedule; Immunogenicity, Vaccine; Middle East Respiratory Syndrome Coronavirus; Pandemics; Patient Safety; Peptidyl-Dipeptidase A; Pneumonia, Viral; Protein Binding; Receptors, Virus; Severe acute respiratory syndrome-related coronavirus; SARS-CoV-2; Severe Acute Respiratory Syndrome; Spike Glycoprotein, Coronavirus; Vaccines, Attenuated; Vaccines, DNA; Vaccines, Subunit; Vaccines, Virus-Like Particle; Viral Vaccines
PubMed: 33051445
DOI: 10.1038/s41392-020-00352-y -
Journal of Autism and Developmental... Aug 2021The S100 calcium-binding protein beta subunit (S100B) protein, which mostly exists in the central nervous system, is commonly noted as a marker of neuronal damage. We... (Meta-Analysis)
Meta-Analysis
The S100 calcium-binding protein beta subunit (S100B) protein, which mostly exists in the central nervous system, is commonly noted as a marker of neuronal damage. We conducted the first systematic review with meta-analysis to compare peripheral blood S100B levels in individuals with ASD with those in healthy controls. A systematic search was carried out for studies published before May 5, 2020. In total, this meta-analysis involved ten studies with 822 participants and 451 cases. The meta-analysis revealed that individuals with ASD had higher peripheral blood S100B levels than healthy controls [standardized mean difference (SMD) = 0.97, 95% confidence interval (95% CI) = 0.41-1.53; p < 0.001]. Peripheral blood S100B levels may have potential as a useful biomarker for ASD.
Topics: Adolescent; Autism Spectrum Disorder; Biomarkers; Child; Child, Preschool; Female; Humans; Male; S100 Calcium Binding Protein beta Subunit
PubMed: 33006697
DOI: 10.1007/s10803-020-04710-1 -
The Journal of International Medical... Aug 2020Interleukin-12 (IL-12) is considered to be a risk factor for cancer; however, its role in hepatocellular carcinoma (HCC) remains unknown. This study aimed to explore the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Interleukin-12 (IL-12) is considered to be a risk factor for cancer; however, its role in hepatocellular carcinoma (HCC) remains unknown. This study aimed to explore the impacts of the IL-12 rs3212227 and rs568408 gene polymorphisms on HCC.
METHODS
We searched PubMed, Embase, Web of Science, and Chinese Knowledge Infrastructure databases for studies on the associations between HCC and IL-12 rs568408 and rs3212227 polymorphisms published prior to 1 May 2020. The effects of the polymorphisms on HCC susceptibility were presented as odds ratios (ORs) and associated 95% confidence intervals.
RESULTS
Seven studies were ultimately included, including 2375 cases and 3445 controls. The rs3212227 polymorphism was significantly associated with the risk of HCC in both the dominant model (CC+AC vs. AA, OR=1.22) and the allele model (C vs. A, OR=1.12). Combined analysis of rs568408 yielded a significant relative risk for HCC in the dominant (AA+AG vs. GG, OR=1.13), recessive (AA vs. AG+GG, OR=1.72), allele (A vs. G, OR=1.29), heterozygote (AG vs. GG, OR=1.27), and homozygote models (AA vs. GG, OR 1.17).
CONCLUSION
The IL-12 rs3212227 and rs568408 gene polymorphisms are associated with an increased risk of HCC.
Topics: Carcinoma, Hepatocellular; Genetic Predisposition to Disease; Humans; Interleukin-12; Interleukin-12 Subunit p35; Liver Neoplasms; Polymorphism, Single Nucleotide; Risk Factors
PubMed: 32809897
DOI: 10.1177/0300060520943420 -
BioMed Research International 2020Arsenic is a toxic metalloid widely present in nature, and arsenic poisoning in drinking water is a serious global public problem. Glutathione is an important reducing...
BACKGROUND
Arsenic is a toxic metalloid widely present in nature, and arsenic poisoning in drinking water is a serious global public problem. Glutathione is an important reducing agent that inhibits arsenic-induced oxidative stress and participates in arsenic methylation metabolism. Therefore, glutathione plays an important role in regulating arsenic toxicity. In recent years, a large number of studies have shown that arsenic can regulate glutathione synthesis in many ways, but there are many contradictions in the research results. At present, the mechanism of the effect of arsenic on glutathione synthesis has not been elucidated.
OBJECTIVE
We will conduct a meta-analysis to illustrate the effects of arsenic on GSH synthesis precursors Glu, Cys, Gly, and rate-limiting enzyme -GCS in mammalian models, as well as the regulation of p38/Nrf2 of -GCS subunit GCLC, and further explore the molecular mechanism of arsenic affecting glutathione synthesis.
RESULTS
This meta-analysis included 30 studies in vivo and 58 studies in vitro, among which in vivo studies showed that arsenic exposure could reduce the contents of GSH (SMD = -2.86, 95% CI (-4.45, -1.27)), Glu (SMD = -1.11, 95% CI (-2.20,-0.02)), and Cys (SMD = -1.48, 95% CI (-2.63, -0.33)), with no statistically significant difference in p38/Nrf2, GCLC, and GCLM. In vitro studies showed that arsenic exposure increased intracellular GSH content (SMD = 1.87, 95% CI (0.18, 3.56)) and promoted the expression of p-p38 (SMD = 4.19, 95% CI (2.34, 6.05)), Nrf2 (SMD = 4.60, 95% CI (2.34, 6.86)), and GCLC (SMD = 1.32, 95% CI (0.23, 2.41)); the p38 inhibitor inhibited the expression of Nrf2 (SMD = -1.27, 95% CI (-2.46, -0.09)) and GCLC (SMD = -5.37, 95% CI (-5.37, -2.20)); siNrf2 inhibited the expression of GCLC, and BSO inhibited the synthesis of GSH. There is a dose-dependent relationship between the effects of exposure on GSH in vitro. These indicate the difference between in vivo and in vitro studies of the effect of arsenic on glutathione synthesis. In vivo studies have shown that arsenic exposure can reduce glutamate and cysteine levels and inhibit glutathione synthesis, while in vitro studies have shown that chronic low-dose arsenic exposure can activate the p38/Nrf2 pathway, upregulate GCLC expression, and promote glutathione synthesis.
Topics: Animals; Arsenic; Arsenic Poisoning; Glutamate-Cysteine Ligase; Glutathione; Humans; NF-E2-Related Factor 2; Oxidative Stress
PubMed: 32802886
DOI: 10.1155/2020/9414196