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.
Almost daily we hear news stories, advertisements, and scientific reports that promise genetic medicine will make us live longer, enable doctors to identify and treat diseases before they start, and ...individualize our medical care. But surprisingly, a century ago eugenicists were making the same promises.The Science of Human Perfectiontraces the history of the promises of medical genetics and of the medical dimension of eugenics. The book also considers social and ethical issues that cast troublesome shadows over these fields.
Keeping his focus on America, science historian Nathaniel Comfort introduces the community of scientists, physicians, and public health workers who have contributed to the development of medical genetics from the nineteenth century to today. He argues that medical genetics is closely related to eugenics, and indeed the two cannot be fully understood separately. He also carefully examines how the desire to relieve suffering and to improve ourselves genetically, though noble, may be subverted. History makes clear that as patients and consumers we must take ownership of genetic medicine, using it intelligently, knowledgeably, and skeptically, lest pernicious interests trump our own.
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.
![WNT16 Requires G[alpha] Sub...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0171-967X/small "WNT16 Requires G[alpha] Subunits as Intracellular Partners for Both Its Canonical and Non-Canonical WNT Signalling Activity in Osteoblasts")
