Late-onset Fuchs endothelial corneal dystrophy (FECD) is a disease affecting the corneal endothelium (CE), associated with a cytosine-thymine-guanine repeat expansion at the CTG18.1 locus in the ...transcription factor 4 (TCF4) gene. It is unknown whether CTG18.1 expansions affect global methylation including TCF4 gene in CE or whether global CE methylation changes at advanced age. Using genome-wide DNA methylation array, we investigated methylation in CE from FECD patients with CTG18.1 expansions and studied the methylation in healthy CE at different ages. The most revealing DNA methylation findings were analyzed by gene expression and protein analysis. 3488 CpGs had significantly altered methylation pattern in FECD though no substantial changes were found in TCF4. The most hypermethylated site was in a predicted promoter of aquaporin 1 (AQP1) gene, and the most hypomethylated site was in a predicted promoter of coagulation factor V (F5 for gene, FV for protein). In FECD, AQP1 mRNA expression was variable, while F5 gene expression showed a ~ 23-fold increase. FV protein was present in both healthy and affected CE. Further gene expression analysis of coagulation factors interacting with FV revealed a ~ 34-fold increase of thrombomodulin (THBD). THBD protein was detected only in CE from FECD patients. Additionally, we observed an age-dependent hypomethylation in elderly healthy CE.Thus, tissue-specific genome-wide and gene-specific methylation changes associated with altered gene expression were discovered in FECD. TCF4 pathological methylation in FECD because of CTG18.1 expansion was ruled out.
Keywords: Wnt16; WNT signalling; Osteoblasts; Galpha subunits In the past years, WNT16 became an interesting target in the field of skeletal research, as it was identified as an essential regulator ...of the cortical bone compartment, with the ability to increase both cortical and trabecular bone mass and strength in vivo. Even though there are indications that these advantageous effects are coming from canonical and non-canonical WNT-signalling activity, a clear model of WNT signalling by WNT16 is not yet depicted. We, therefore, investigated the modulation of canonical (WNT/beta-catenin) and non-canonical WNT/calcium, WNT/planar cell polarity (PCP) signalling in human embryonic kidney (HEK) 293 T and SaOS2 cells. Here, we demonstrated that WNT16 activates all WNT-signalling pathways in osteoblasts, whereas only WNT/calcium signalling was activated in HEK293T cells. In osteoblasts, we therefore, additionally investigated the role of Galpha subunits as intracellular partners in WNT16 s mechanism of action by performing knockdown of Galpha12, Galpha13 and Galphaq. These studies point out that the above-mentioned Galpha subunits might be involved in the WNT/beta-catenin and WNT/calcium-signalling activity by WNT16 in osteoblasts, and for Galpha12 in its WNT/PCP-signalling activity, illustrating a novel possible mechanism of interplay between the different WNT-signalling pathways in osteoblasts. Additional studies are needed to demonstrate whether this mechanism is specific for WNT16 signalling or relevant for all other WNT ligands as well. Altogether, we further defined WNT16 s mechanism of action in osteoblasts that might underlie the well-known beneficial effects of WNT16 on skeletal homeostasis. These findings on WNT16 and the activity of specific Galpha subunits in osteoblasts could definitely contribute to the development of novel therapeutic approaches for fragility fractures in the future. Author Affiliation: (1) Department of Medical Genetics, University of Antwerp, Antwerp, Belgium (2) Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (3) Department of Medical Genetics, University of Antwerp, Prins Boudewijnlaan 43, Edegem, 2650, Antwerp, Belgium (f) wim.vanhul@uantwerpen.be Article History: Registration Date: 11/11/2019 Received Date: 08/02/2019 Accepted Date: 11/11/2019 Online Date: 11/23/2019 Byline: Gretl Hendrickx (1, 2), Eveline Boudin (1), Marinus Verbeek (1), Erik Fransen (1), Geert Mortier (1), Wim Van Hul (corresponding author) (1, 3, f)
This study, conducted in the Republic of North Ossetia-Alania (RNOA), aimed to explore the genetic landscape of hyperphenylalaninemia (HPA) and phenylketonuria (PKU) in the Ossetian population using ...data from newborn screening (NBS). Through comprehensive molecular genetic analysis of 29 patients with HPA from diverse ethnic backgrounds, two major genetic variants in the PAH gene, P281L and P211T, were identified, constituting 50% of all detected pathogenic alleles in Ossetian patients. Remarkably, these variants exhibited an exceptionally high frequency in the Ossetian population, surpassing global prevalence rates. This study unveiled a notable prevalence of mild forms of HPA (78%), underscoring the importance of genetic counseling for carriers of pathogenic variants in the PAH gene. Moreover, the findings emphasized the necessity for ongoing monitoring of patients with mild forms, as they may lack significant symptoms for diagnosis, potentially impacting offspring. Overall, this research offers valuable insights into the genetic landscape of HPA and PKU in the Ossetian population.
Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a critical
role in Alzheimer’s disease (AD) pathogenesis. This study aimed to investigate
the relationship between microRNA-149 ...(miR-149) and BACE1, and evaluate the
clinical significance and biological function of miR-149 in AD progression.
Bioinformatics analysis and a luciferase reporter assay were used to confirm the
interaction between miR-149 and BACE1. Expression of miR-149 and BACE1 was
estimated using quantitative real-time PCR. The clinical significance of miR-149
in AD diagnosis and severity determination was evaluated using ROC analysis. The
effect of miR-149 on Aβ accumulation and neuronal viability was analyzed in
Aβ-treated SH-SY5Y cells. miR-149 was found directly binding the 3’-UTR of BACE1
and was negatively correlated with BACE1 in AD patients and cell model. Serum
miR-149 expression was downregulated in AD patients and served as a potential
diagnostic biomarker. The overexpression of miR-149 in Aβ-treated SH-SY5Y cells
resulted in inhibited Aβ accumulation and enhanced neuronal viability. This
study demonstrated that serum miR-149 is decreased in AD patients and serves as
a candidate diagnostic biomarker, and that the overexpression of miR-149 may
suppress Aβ accumulation and promote neuronal viability by targeting BACE1 in AD
model cells.
MicroRNAs represent a class of small RNAs derived from polymerase II controlled transcriptional regions. The primary transcript forms one or several bulging double stranded hairpins which are ...processed by Drosha and Dicer into hetero-duplexes. The targeting microRNA strand of the duplex is incorporated into the RNA Induced Silencing Complex from where it silences up to hundreds of mRNA transcript by inducing mRNA degradation or blocking protein translation. Apart from involvement in a variety of biological processes, microRNAs were early recognized for their potential in disease diagnostics and therapeutics. Due to their stability, microRNAs could be used as biomarkers. Currently, there are microRNA panels helping physicians determining the origins of cancer in disseminated tumors. The development of microRNA therapeutics has proved more challenging mainly due to delivery issues. However, one drug is already in clinical trials and several more await entering clinical phases. This review summarizes what has been recognized pre-clinically and clinically on diagnostic microRNAs. In addition, it highlights individual microRNA drugs in running platforms driven by four leading microRNA-therapeutic companies.
Primary immunodeficiencies (PID) are a diverse group of genetic disorders caused by inadequate development and function of immune system. Identifying genetic etiology is important for genetic ...counselling and treatment decisions. Clinical relevance of genetic variants is a complex problem depending on gene-specific and variant specific genotype-phenotype interactions. To address this challenge, we aimed to characterize the pathogenic landscape of PID genes by combining the analysis of germline variations reported in ClinVar and HGMD.sup.® and identification of damaging variations available in dbSNP. We generated a joint ClinVar/HGMD database, which included 111,940 variants, among them 32,452 were classified as pathogenic/likely pathogenic. From a total of 5,415,794 bi- or multiallelic variants in PID genes recorded in dbSNP, we retrieved 38,291 high impact (HI) biallelic variants with presumably disruptive impact in the protein, of them 25,500 variants were not present in ClinVar/HGMD. Using a functional prediction algorithm, we additionally identified 28,507 deleterious and 56,016 neutral missense variants among dbSNP variants and created a collection of damaging and neutral variations in PID genes, not currently present in ClinVar/HGMD, with their allele frequencies and mappings to protein domains. The distribution of pathogenic variants from ClinVar/HGMD, HI variants and deleterious missense variants from dbSNP was analyzed in the context of hereditary pattern and gene specific metrics, such as pLI and haploinsufficiency. Our report summarized data on complex gene-specific variability in PID genes and might be useful for the identification of the most promising variants and gene regions for further study.
Neurogenetic Disorders Singh, Kuldeep
Indian journal of clinical biochemistry,
05/2022, Letnik:
29, Številka:
S1
Journal Article
Recenzirano
No other system in our human body is so widely affected by genetic conditions as nervous system. The neurological disorders not only baffled the neurologist but are also intriguing the experts in ...genetic conditions. To a general physician what may appear to be a normal variation may be an indicator of an early clinical presentation of a late onset neurogenetic disease. The clinical presentation of a genetic neurological condition may present with clumsiness to behavior problems to frank manifestation of abnormal movements. While clinical phenotype delineation can only be done by an experienced neurologist, the further management of the condition may bewilder even an expert. On the other hand a genetic expert may have wide experience of making a laboratory diagnosis of ever increasing genetic disorders with an armamentarium of genetic tools, he may never come close to provide support to family or community unless precise diagnosis established. Between the two extremes, we may provide working solutions which are not only useful for the patients but also helpful for establishing public health policies for some of these devastating conditions. In effect, this means embarking on an integrated approach for managing such conditions and extending the same to community incorporating into existing public health systems. To simplify the process, step wise approach may be needed with continuous dialogues between clinical biochemist and clinician. There is a need to create awareness about common neurological disorders, their genetic basis and available resources. Basic concepts of genetic counseling, genetic testing, types of diagnostic tests, their optimal utilization and interpretation is important. An environmental condition may mimick a disorder to be genetic. On the other hand a genetic neurological condition may occur due to different mutations located on different chromosomes. Recent advances in approaches to common genetic disorders like epilepsies, dementia, ataxia and movement disorders will be highlighted.
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