The prevalence of type 2 diabetes mellitus (T2DM) is increasing dramatically worldwide. Dysregulation of microRNA (miRNA) as key regulators of gene expression, has been reported in numerous diseases ...including diabetes. The aim of this study was to investigate the expression levels of miRNA-122, miRNA-126-3p and miRNA-146a in diabetic and pre-diabetic patients and in healthy individuals, and to determine whether the changes in the level of these miRNAs are reliable biomarkers in diagnosis, prognosis, and pathogenesis of T2DM. Additionally, we examined the relationship between miRNA levels and plasma concentrations of inflammatory factors including tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (Il-6) as well as insulin resistance. In this case-control study, participants (n = 90) were allocated to three groups (n = 30/group): T2DM, pre-diabetes and healthy individuals as control (males and females, age: 25-65, body mass index: 25-35). Expression of miRNA was determined by real-time polymerase chain reaction (RT-PCR). Furthermore, plasma concentrations of TNF-alpha, IL-6 and fasting insulin were measured by enzyme-linked immunosorbent assay. Homeostatic model assessment for insulin resistance (HOMA-IR) was calculated as an indicator of insulin resistance. MiRNA-122 levels were higher while miRNA-126-3p and miRNA-146a levels were lower in T2DM and pre-diabetic patients compared to control (p<0.05). Furthermore, a positive correlation was found between miRNA-122 expression and TNF-alpha (r = 0.82), IL-6 (r = 0.83) and insulin resistance (r = 0.8). Conversely, negative correlations were observed between miRNA-126-3p and miRNA-146a levels and TNF-alpha (r = -0.7 and r = -0.82 respectively), IL-6 (r = -0.65 and r = -0.78 respectively) as well as insulin resistance (r = -0.67 and r = -0.78 respectively) (all p<0.05). Findings of this study suggest the miRNAs can potentially contribute to the pathogenesis of T2DM. Further studies are required to examine the reproducibility of these findings.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Variants in the Aristaless‐related homeobox (ARX) gene lead to a variety of phenotypes, with intellectual disability being a steady feature. Other features can include severe epilepsy, ...spasticity, movement disorders, hydranencephaly, and ambiguous genitalia in males. X‐linked Ohtahara syndrome or Type 1 early infantile epileptic encephalopathy (EIEE1) is a severe early‐onset epileptic encephalopathy with arrested psychomotor development caused by hemizygous mutations in the ARX gene, which encodes a transcription factor in fundamental brain developmental processes.
Methods
We presented a case report of a 2‐year‐old boy who exhibited symptoms such as microcephaly, seizures, and severe multifocal epileptic abnormalities, and genetic techniques such as autozygosity mapping, Sanger sequencing, and whole‐exome sequencing.
Results
We confirmed that the patient had the NM_139058.3:c.84C>A; p.(Cys28Ter) mutation in the ARX gene.
Conclusion
The patient with EIEE1 had physical symptoms and hypsarrhythmia on electroencephalogram. Genetic testing identified a causative mutation in the ARX gene, emphasizing the role of genetic testing in EIEE diagnosis.
Variants in Aristaless‐related homeobox (ARX) gene lead to a variety of phenotypes with intellectual disability being a steady feature. Other features can include severe epilepsy, spasticity, movement disorders, hydranencephaly, and ambiguous genitalia in males. Ohtahara syndrome or Type 1 early infantile epileptic encephalopathy is a severe early‐onset epileptic encephalopathy with arrest of psychomotor development caused by hemizygous mutations in the ARX gene, which encodes a transcription factor in fundamental brain developmental processes. We presented a case report of 2‐year‐old boy, which indicates symptoms of Ohtahara syndrome.
Pontocerebellar hypoplasia (PCH) describes a group of rare heterogeneous neurodegenerative diseases with prenatal onset. Here we describe eight children with PCH from four unrelated families ...harboring the homozygous MINPP1 (NM_004897.4) variants; c.75_94del, p.(Leu27Argfs*39), c.851 C > A, p.(Ala284Asp), c.1210 C > T, p.(Arg404*), and c.992 T > G, p.(Ile331Ser). The homozygous p.(Leu27Argfs*39) change is predicted to result in a complete absence of MINPP1. The p.(Arg404*) would likely lead to a nonsense mediated decay, or alternatively, a loss of several secondary structure elements impairing protein folding. The missense p.(Ala284Asp) affects a buried, hydrophobic residue within the globular domain. The introduction of aspartic acid is energetically highly unfavorable and therefore predicted to cause a significant reduction in protein stability. The missense p.(Ile331Ser) affects the tight hydrophobic interactions of the isoleucine by the disruption of the polar side chain of serine, destabilizing the structure of MINPP1. The overlap of the above-mentioned genotypes and phenotypes is highly improbable by chance. MINPP1 is the only enzyme that hydrolyses inositol phosphates in the endoplasmic reticulum lumen and several studies support its role in stress induced apoptosis. The pathomechanism explaining the disease mechanism remains unknown, however several others genes of the inositol phosphatase metabolism (e.g., INPP5K, FIG4, INPP5E, ITPR1) are correlated with phenotypes of neurodevelopmental disorders. Taken together, we present MINPP1 as a novel autosomal recessive pontocerebellar hypoplasia gene.
Type 2 diabetes mellitus (T2DM) is a heritable metabolic perturbation, rapidly growing across the world. Primary recognition of susceptible individuals with a family history of type 2 diabetes (FHD) ...in the prediabetes stage could delay the onset of T2DM or reduce complications induced by diabetes. This study aims to evaluate the expression levels of miR‐21, miR‐126 as noninvasive predictive biomarkers in individuals with genetic predisposition and investigate the correlation of miRNAs and cardiometabolic risk factors. Our study demonstrated that miR‐21 expression has a notable elevate in both groups of T2DM and pre‐T2DM. miR‐21 expression was distinguished in the pre‐T2DM and T2DM from the nondiabetic individuals by ROC curve analysis with AUC of 0.77 (95% CI 0.65–0.90; p = 0.0004) and AUC of 0.78 (95% CI 0.64–0.92; p = 0.0042), respectively. The relative gene expression of miR‐126 was nearly equal among groups. miR‐21 expression was positively associated with glycosylated hemoglobin (HbA1c), fasting blood sugar (FBS), and triglyceride (TG) and might have diagnostic value for T2DM and pre‐T2DM. This study has revealed that the expression level of miR‐21 can be considered as a non‐invasive and rapid tool for distinguishing pre‐T2DM and T2DM counterparts from healthy individuals.
MicroRNAs in pre‐T2DM and T2DM: miR‐21 as a potential biomarker in pre‐T2DM and T2DM.
The dramatic increase in the prevalence of type 2 diabetes mellitus (T2DM) is a global major challenge to health. Circulating microRNAs have been suggested as promising biomarkers for different ...disorders such as diabetes. Imbalances in the gut microbiome have been revealed to contribute to the progression of multiple diseases including T2DM. Recently, the consumption of probiotics and synbiotics in the treatment of various diseases has shown a substantial growth. The anti-diabetes and anti-inflammatory effects of synbiotics have been indicated, which may be due to their beneficial effects on the gut microbiome. However, further research is needed to assess the effects of synbiotics on the microbiota and their impacts on expression of microRNAs relating to T2DM. Thus, we will aim to assess the effects of synbiotics on microbiota, serum level of tumor necrosis factor-α (TNF-α), and expression of microRNA-126 and microRNA-146a in patients with T2DM.
Seventy-two patients with T2DM will be recruited in this double-blind randomized parallel placebo-controlled clinical trial. After block matching based on age and sex, participants will be randomly assigned to receive 1000 mg/day synbiotic (Familact) or placebo for 12 weeks. The microRNA-126 and microRNA-146a expression levels will be measured by real-time polymerase chain reaction and serum TNF-α level will be assessed by enzyme-linked immunosorbent assay kit at the beginning and at the end of the study. Determination of the gut microbiota will be done by quantitative polymerase chain reaction methods at baseline and at the end of the trial. Biochemical assessments (glycemic and lipid profiles) will also be conducted at onset and end of the study.
This is the first randomized controlled trial that will determine the effect of synbiotic supplementation on the gut microbiota and its probable impacts on serum levels of TNF-α and expression of related microRNAs in patients with T2DM.
Iranian Registry of Clinical Trials: IRCT20180624040228N2. Registered on 27 March 2019. http://www.irct.ir/trial/38371.
Background
Intellectual disability (ID) is a heterogeneous group of neurodevelopmental disorders that is characterized by significant impairment in intellectual and adaptive functioning with onset ...during the developmental period. Whole‐exome sequencing (WES)‐based studies in the consanguineous families with individuals affected with ID have shown a high burden of relevant variants. So far, over 700 genes have been reported in syndromic and non‐syndromic ID. However, genetic causes in more than 50% of ID patients still remain unclear.
Methods
Whole‐exome sequencing was applied for investigation of various variants of ID, then Sanger sequencing and in silico analysis in ten patients from five Iranian consanguineous families diagnosed with autosomal recessive neurodevelopmental disorders, intellectual disability, performed for confirming the causative mutation within the probands. The most patients presented moderate‐to‐severe intellectual disability, developmental delay, seizure, speech problem, high level of lactate, and onset before 10 years.
Results
Filtering the data identified by WES, two novel homozygous missense variants in FBXO31 and TIMM50 genes and one previously reported mutation in the CEP290 gene in the probands were found. Sanger sequencing confirmed the homozygote variant's presence of TIMM50 and FBXO31 genes in six patients and two affected siblings in their respective families. Our computational results predicted that the variants are located in the conserved regions across different species and have the impacts on the protein stability.
Conclusion
Hence, we provide evidence for the pathogenicity of two novel variants in the patients which will expand our knowledge about potential mutation involved in the heterogeneous disease.
Biallelic variants of the gene encoding for the zinc‐finger protein 142 (ZNF142) have recently been associated with intellectual disability (ID), speech impairment, seizures, and movement disorders ...in nine individuals from five families. In this study, we obtained phenotype and genotype information of 26 further individuals from 16 families. Among the 27 different ZNF142 variants identified in the total of 35 individuals only four were missense. Missense variants may give a milder phenotype by changing the local structure of ZF motifs as suggested by protein modeling; but this correlation should be validated in larger cohorts and pathogenicity of the missense variants should be investigated with functional studies. Clinical features of the 35 individuals suggest that biallelic ZNF142 variants lead to a syndromic neurodevelopmental disorder with mild to moderate ID, varying degrees of delay in language and gross motor development, early onset seizures, hypotonia, behavioral features, movement disorders, and facial dysmorphism. The differences in symptom frequencies observed in the unpublished individuals compared to those of published, and recognition of previously underemphasized facial features are likely to be due to the small sizes of the previous cohorts, which underlines the importance of larger cohorts for the phenotype descriptions of rare genetic disorders.
Zinc‐finger protein 142, encoded by ZNF142, belongs to a family transcriptional repressors that recruit chromatin remodeling proteins to DNA. They are widely expressed and are important for numerous processes such as development, cell differentiation and proliferation, and apoptosis. Zn2+ ions (gray) and three modellable missense variants (yellow) are depicted as spheres.
Endometriosis is a female reproductive system disease in which the endometrial tissue is found in other women's organs. Various factors are effective in the development of endometriosis, and because ...of the interaction of genetics and environmental factors, this disease is a multi-factorial disease. MAPK/ERK and PI3K/Akt/mTOR pathways are activated by growth factors and steroid hormones and are known as two important pathways involved in the processes of growth, proliferation, and survival of endometriosis cells. Raps, monomeric GTPase of the Ras family, are able to activate these pathways independent of Ras. The goal of our study was to evaluate the expression level of
and
genes as two important RapGAPs (GTPase-activating proteins) and RapGEFs (guanine nucleotide exchange factors), respectively, in endometriosis tissues and normal endometrium tissues.
In this study, 15 samples of women without signs of endometriosis were taken as control samples. Fifteen ectopic and 15 eutopic samples were taken from women with endometriosis using laparoscopic surgery. The expression of
and
genes was investigated by the real-time polymerase chain reaction technique, and the results were analyzed by one-way ANOVA test.
upregulated significantly in ectopic tissues compared to eutopic and control tissues.
expression was lower in ectopic tissues compared to control and eutopic tissues.
Based on these results, it may be concluded that changes in the expression of the
and Epca1 genes may play a role in the pathways involved in the pathogenesis, displacement, and migration of endometriosis cells.
In recent years, considerable attention has been paid to the role of microRNAs (miRs) as biomarkers in type 2 diabetes (T2D). The aim of the study was to evaluate the expression levels of miR-15a and ...miR-222 in diabetic, pre-diabetic, and healthy individuals.
Ninety individuals, who were referred to the Yazd diabetic center, were enrolled in this study and then classified into three groups as healthy, pre-T2D, and diabetic based on the clinical manifestations. Real-time PCR was performed to explore miRs expression in the plasma samples of the studied population. The correlation between the biochemical characteristic and the expression of these miRs as well as specificity and sensitivity of different clinical markers in healthy and pre-diabetic groups was evaluated.
miR-222 expression was significantly upregulated in the pre-T2D cases compared to the control subjects (P<0.001), while no significant difference was found between the pre-T2D and T2D groups (P<0.05). The expression of miR-15a was statistically downregulated in the pre-T2D and T2D subjects (P<0.05). The receiver operating characteristic (ROC) curve analysis of miR-15a expression with a cutoff point of 1.12 resulted in the area under the curve (AUC) of 85% (95% CI 0.865-0.912; P<0.001) with 84% and 85% sensitivity and specificity, respectively. Similarly, for miR-222, the cutoff point of 4.03 and AUC of 86% (95% CI 0.875-0.943; P<0.001) discriminated against the pre-T2D and control subjects via the sensitivity and specificity of 86% and 87%, respectively. Moreover, miR-15a values showed a negative correlation with FG (R=-0.32, P=0.005); however, miR-222 values were positively correlated with FG (R=0.25, P=0.03) in the pre-T2D group. Furthermore, miR-222 values were correlated with OGTT in the pre-T2D group (R=0.27, P=0.001). In addition, LDL-C had a negative correlation with miR-222 values in the pre-T2D group (R=-0.23, P=0.02).
This study indicated that the plasma expression levels of miR-222 and miR-15a can be considered as non-invasive, fast tools to separate the pre-T2D individuals from their healthy counterparts. Accordingly, this information could be used to predict the development of the disease as well as a direction for optimal therapy, thus refining outcomes in patients with diabetes.
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