-
Biomedicines Mar 2024Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. It follows an autosomal dominant inheritance pattern in most cases, with incomplete... (Review)
Review
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. It follows an autosomal dominant inheritance pattern in most cases, with incomplete penetrance and heterogeneity. It is familial in 60% of cases and most of these are caused by pathogenic variants in the core sarcomeric genes (, , , , , , , ). Genetic testing using targeted disease-specific panels that utilize next-generation sequencing (NGS) and include sarcomeric genes with the strongest evidence of association and syndrome-associated genes is highly recommended for every HCM patient to confirm the diagnosis, identify the molecular etiology, and guide screening and management. The yield of genetic testing for a disease-causing variant is 30% in sporadic cases and up to 60% in familial cases and in younger patients with typical asymmetrical septal hypertrophy. Genetic testing remains challenging in the interpretation of results and classification of variants. Therefore, in 2015 the American College of Medical Genetics and Genomics (ACMG) established guidelines to classify and interpret the variants with an emphasis on the necessity of periodic reassessment of variant classification as genetic knowledge rapidly expands. The current guidelines recommend focused cascade genetic testing regardless of age in phenotype-negative first-degree relatives if a variant with decisive evidence of pathogenicity has been identified in the proband. Genetic test results in family members guide longitudinal clinical surveillance. At present, there is emerging evidence for genetic test application in risk stratification and management but its implementation into clinical practice needs further study. Promising fields such as gene therapy and implementation of artificial intelligence in the diagnosis of HCM are emerging and paving the way for more effective screening and management, but many challenges and obstacles need to be overcome before establishing the practical implications of these new methods.
PubMed: 38540296
DOI: 10.3390/biomedicines12030682 -
Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis.Science Advances Feb 2024Folate, an essential vitamin, is a one-carbon acceptor and donor in key metabolic reactions. Erythroid cells harbor a unique sensitivity to folate deprivation, as...
Folate, an essential vitamin, is a one-carbon acceptor and donor in key metabolic reactions. Erythroid cells harbor a unique sensitivity to folate deprivation, as revealed by the primary pathological manifestation of nutritional folate deprivation: megaloblastic anemia. To study this metabolic sensitivity, we applied mild folate depletion to human and mouse erythroid cell lines and primary murine erythroid progenitors. We show that folate depletion induces early blockade of purine synthesis and accumulation of the purine synthesis intermediate and signaling molecule, 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR), followed by enhanced heme metabolism, hemoglobin synthesis, and erythroid differentiation. This is phenocopied by inhibition of folate metabolism using the inhibitor SHIN1, and by AICAR supplementation. Mechanistically, the metabolically driven differentiation is independent of mechanistic target of rapamycin complex 1 (mTORC1) and adenosine 5'-monophosphate-activated protein kinase (AMPK) and is instead mediated by protein kinase C. Our findings suggest that folate deprivation-induced premature differentiation of erythroid progenitor cells is a molecular etiology to folate deficiency-induced anemia.
Topics: Mice; Humans; Animals; Folic Acid; Cell Differentiation; Cell Line; Mechanistic Target of Rapamycin Complex 1; Purines
PubMed: 38295180
DOI: 10.1126/sciadv.adj9479 -
BioRxiv : the Preprint Server For... Jan 2024Loss-of-function mutations in the genes encoding PINK1 and PRKN result in early-onset Parkinson disease (EOPD). Together the encoded enzymes direct a neuroprotective...
Loss-of-function mutations in the genes encoding PINK1 and PRKN result in early-onset Parkinson disease (EOPD). Together the encoded enzymes direct a neuroprotective pathway that ensures the elimination of damaged mitochondria via autophagy. We performed a genome-wide high content imaging miRNA screen for inhibitors of the PINK1-PRKN pathway and identified all three members of the miRNA family 29 (miR-29). Using RNAseq we identified target genes and found that siRNA against ATG9A phenocopied the effects of miR-29 and inhibited the initiation of PINK1-PRKN mitophagy. Furthermore, we discovered two rare, potentially deleterious, missense variants (p.R631W and p.S828L) in our EOPD cohort and tested them experimentally in cells. While expression of wild-type ATG9A was able to rescue the effects of miR-29a, the EOPD-associated variants behaved like loss-of-function mutations. Together, our study validates miR-29 and its target gene ATG9A as novel regulators of mitophagy initiation. It further serves as proof-of-concept of finding novel, potentially disease-causing EOPD-linked variants specifically in mitophagy regulating genes. The nomination of genetic variants and biological pathways is important for the stratification and treatment of patients that suffer from devastating diseases, such as EOPD.
PubMed: 38293184
DOI: 10.1101/2024.01.17.576122 -
Journal of Thrombosis and Haemostasis :... May 2024Endoplasmic reticulum (ER) stress is a key feature of lipid-laden macrophages and contributes to the development of atherosclerotic plaques. Blood platelets are known to...
BACKGROUND
Endoplasmic reticulum (ER) stress is a key feature of lipid-laden macrophages and contributes to the development of atherosclerotic plaques. Blood platelets are known to interact with macrophages and fine-tune effector functions such as inflammasome activation and phagocytosis. However, the effect of platelets on ER stress induction is unknown.
OBJECTIVES
The objective of this study is to elucidate the potential of platelets in regulating ER stress in macrophages in vitro.
METHODS
Bone marrow-derived macrophages and RAW 264.7 cells were incubated with isolated murine platelets, and ER stress and inflammation markers were determined by reverse transcription-quantitative polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay. ER morphology was investigated by electron microscopy. Cell viability, lipid accumulation, and activation were measured by flow cytometry. To gain mechanistic insights, coincubation experiments were performed with platelet decoys/releasates as well as lipopolysaccharide, blocking antibodies, and TLR4 inhibitors.
RESULTS
Coincubation of platelets and macrophages led to elevated levels of ER stress markers (BIP, IRE1α, CHOP, and XBP1 splicing) in murine and human macrophages, which led to a pronounced enlargement of the ER. Macrophage ER stress was accompanied by increased release of proinflammatory cytokines and intracellular lipid accumulation, but not cell death. Platelet decoys, but not platelet releasates or lysate from other cells, phenocopied the effect of platelets. Blocking TLR4 inhibited inflammatory activation of macrophages but did not affect ER stress induction by platelet coincubation.
CONCLUSION
To our knowledge, this study is the first to demonstrate that platelets induce ER stress and unfolded protein response in macrophages by heat-sensitive membrane proteins, independent of inflammatory activation of macrophages.
Topics: Animals; Endoplasmic Reticulum Stress; Blood Platelets; Macrophages; Humans; Mice; RAW 264.7 Cells; X-Box Binding Protein 1; Mice, Inbred C57BL; Toll-Like Receptor 4; Endoplasmic Reticulum; Endoribonucleases; Cytokines; Endoplasmic Reticulum Chaperone BiP; Transcription Factor CHOP; Signal Transduction; Lipopolysaccharides; Heat-Shock Proteins; Lipid Metabolism; Inflammation Mediators; Inflammation; Cell Survival; Protein Serine-Threonine Kinases
PubMed: 38278417
DOI: 10.1016/j.jtha.2024.01.009 -
The Canadian Journal of Cardiology May 2024In this article some of the recent advances in the use of noninvasive imaging applied to patients with hypertrophic cardiomyopathy (HCM) are discussed. Echocardiography... (Review)
Review
In this article some of the recent advances in the use of noninvasive imaging applied to patients with hypertrophic cardiomyopathy (HCM) are discussed. Echocardiography and cardiac computed tomography are briefly discussed with respect to their power to detect apical aneurysmal disease. Echocardiographic phenotype-genotype correlations and the use of echocardiography to characterize myocardial work are reviewed. Positron emission tomography is reviewed in the context of ischemia imaging and also in the context of the use of a new tracer that might allow for recognition of early activation of the fibrosis pathway. Next, the technical capabilities of cardiovascular magnetic resonance to measure myocardial perfusion, oxygenation, and disarray are discussed as they apply to HCM. The application of radiomics to improve prediction of sudden cardiac death is touched upon. Finally, a deep learning approach to the recognition of HCM vs phenocopies is presented as a potential future diagnostic aid in the not-too-distant future.
Topics: Humans; Cardiomyopathy, Hypertrophic; Echocardiography; Magnetic Resonance Imaging, Cine; Positron-Emission Tomography
PubMed: 38467329
DOI: 10.1016/j.cjca.2024.02.030 -
Cureus Sep 2023Brugada syndrome (BrS) is a hereditary channelopathy caused by an autosomal dominant mutation in the cardiac sodium channel gene SCN5A alpha subunit. In individuals...
Brugada syndrome (BrS) is a hereditary channelopathy caused by an autosomal dominant mutation in the cardiac sodium channel gene SCN5A alpha subunit. In individuals without structural heart disease, the risk of sudden cardiac death (SCD) increases in this channelopathy with ST-segment elevation in V1-3 precordials. Brugada phenocopy (BrP) is a condition in which transient ST-segment elevations are observed, mimicking BrS electrocardiographic changes, which can occur with electrolyte and metabolic disorder scenarios. In this study, we share a case of BrP that occurred due to hypovolemic hyponatremia and recovered spontaneously with the correction of electrolyte disturbance.
PubMed: 37868457
DOI: 10.7759/cureus.45667 -
The Journal of Neuroscience : the... Mar 2024The sense of touch is crucial for cognitive, emotional, and social development and relies on mechanically activated (MA) ion channels that transduce force into an...
The sense of touch is crucial for cognitive, emotional, and social development and relies on mechanically activated (MA) ion channels that transduce force into an electrical signal. Despite advances in the molecular characterization of these channels, the physiological factors that control their activity are poorly understood. Here, we used behavioral assays, electrophysiological recordings, and various mouse strains (males and females analyzed separately) to investigate the role of the calmodulin-like Ca sensor, caldendrin, as a key regulator of MA channels and their roles in touch sensation. In mice lacking caldendrin ( KO), heightened responses to tactile stimuli correlate with enlarged MA currents with lower mechanical thresholds in dorsal root ganglion neurons (DRGNs). The expression pattern of caldendrin in the DRG parallels that of the major MA channel required for touch sensation, PIEZO2. In transfected cells, caldendrin interacts with and inhibits the activity of PIEZO2 in a manner that requires an alternatively spliced sequence in the N-terminal domain of caldendrin. Moreover, targeted genetic deletion of caldendrin in -expressing DRGNs phenocopies the tactile hypersensitivity of complete KO mice. We conclude that caldendrin is an endogenous repressor of PIEZO2 channels and their contributions to touch sensation in DRGNs.
Topics: Animals; Female; Male; Mice; Ion Channels; Mechanotransduction, Cellular; Neurons; Touch
PubMed: 38262725
DOI: 10.1523/JNEUROSCI.1402-23.2023 -
Cell Reports Sep 2023The Pallidin protein is a central subunit of a multimeric complex called biogenesis of lysosome-related organelles complex 1 (BLOC1) that regulates specific endosomal...
The Pallidin protein is a central subunit of a multimeric complex called biogenesis of lysosome-related organelles complex 1 (BLOC1) that regulates specific endosomal functions and has been linked to schizophrenia. We show here that downregulation of Pallidin and other members of BLOC1 in the surface glia, the Drosophila equivalent of the blood-brain barrier, reduces and delays nighttime sleep in a circadian-clock-dependent manner. In agreement with BLOC1 involvement in amino acid transport, downregulation of the large neutral amino acid transporter 1 (LAT1)-like transporters JhI-21 and mnd, as well as of TOR (target of rapamycin) amino acid signaling, phenocopy Pallidin knockdown. Furthermore, supplementing food with leucine normalizes the sleep/wake phenotypes of Pallidin downregulation, and we identify a role for Pallidin in the subcellular trafficking of JhI-21. Finally, we provide evidence that Pallidin in surface glia is required for GABAergic neuronal activity. These data identify a BLOC1 function linking essential amino acid availability and GABAergic sleep/wake regulation.
PubMed: 37682712
DOI: 10.1016/j.celrep.2023.113025 -
Science Advances Feb 2024Physiologically, FoxA1 plays a key role in liver differentiation and development, and pathologically exhibits an oncogenic role in prostate and breast cancers. However,...
Physiologically, FoxA1 plays a key role in liver differentiation and development, and pathologically exhibits an oncogenic role in prostate and breast cancers. However, its role and upstream regulation in liver tumorigenesis remain unclear. Here, we demonstrate that FoxA1 acts as a tumor suppressor in liver cancer. Using a CRISPR-based kinome screening approach, noncanonical inflammatory kinase IKBKE has been identified to inhibit FoxA1 transcriptional activity. Notably, IKBKE directly binds to and phosphorylates FoxA1 to reduce its complex formation and DNA interaction, leading to elevated hepatocellular malignancies. Nonphosphorylated mimic knock-in mice markedly delay liver tumorigenesis in hydrodynamic transfection murine models, while phospho-mimic knock-in phenocopy knockout mice to exhibit developmental defects and liver inflammation. Notably, knockout delays diethylnitrosamine (DEN)-induced mouse liver tumor development. Together, our findings not only reveal FoxA1 as a bona fide substrate and negative nuclear effector of IKBKE in hepatocellular carcinioma (HCC) but also provide a promising strategy to target IKBEK for HCC therapy.
Topics: Animals; Male; Mice; Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; Hepatocyte Nuclear Factor 3-alpha; Liver Neoplasms; Mice, Knockout
PubMed: 38324694
DOI: 10.1126/sciadv.adk2285 -
Frontiers in Psychiatry 2023Much recent attention has been directed toward the spatial organization of the cell nucleus and the manner in which three-dimensional topologically associated domains... (Review)
Review
Perturbation of 3D nuclear architecture, epigenomic dysregulation and aging, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 1-aging and epigenomics.
Much recent attention has been directed toward the spatial organization of the cell nucleus and the manner in which three-dimensional topologically associated domains and transcription factories are epigenetically coordinated to precisely bring enhancers into close proximity with promoters to control gene expression. Twenty lines of evidence robustly implicate cannabinoid exposure with accelerated organismal and cellular aging. Aging has recently been shown to be caused by increased DNA breaks. These breaks rearrange and maldistribute the epigenomic machinery to weaken and reverse cellular differentiation, cause genome-wide DNA demethylation, reduce gene transcription, and lead to the inhibition of developmental pathways, which contribute to the progressive loss of function and chronic immune stimulation that characterize cellular aging. Both cell lineage-defining superenhancers and the superanchors that control them are weakened. Cannabis exposure phenocopies the elements of this process and reproduces DNA and chromatin breakages, reduces the DNA, RNA protein and histone synthesis, interferes with the epigenomic machinery controlling both DNA and histone modifications, induces general DNA hypomethylation, and epigenomically disrupts both the critical boundary elements and the cohesin motors that create chromatin loops. This pattern of widespread interference with developmental programs and relative cellular dedifferentiation (which is pro-oncogenic) is reinforced by cannabinoid impairment of intermediate metabolism (which locks in the stem cell-like hyper-replicative state) and cannabinoid immune stimulation (which perpetuates and increases aging and senescence programs, DNA damage, DNA hypomethylation, genomic instability, and oncogenesis), which together account for the diverse pattern of teratologic and carcinogenic outcomes reported in recent large epidemiologic studies in Europe, the USA, and elsewhere. It also accounts for the prominent aging phenotype observed clinically in long-term cannabis use disorder and the 20 characteristics of aging that it manifests. Increasing daily cannabis use, increasing use in pregnancy, and exponential dose-response effects heighten the epidemiologic and clinical urgency of these findings. Together, these findings indicate that cannabinoid genotoxicity and epigenotoxicity are prominent features of cannabis dependence and strongly indicate coordinated multiomics investigations of cannabinoid genome-epigenome-transcriptome-metabolome, chromatin conformation, and 3D nuclear architecture. Considering the well-established exponential dose-response relationships, the diversity of cannabinoids, and the multigenerational nature of the implications, great caution is warranted in community cannabinoid penetration.
PubMed: 37732074
DOI: 10.3389/fpsyt.2023.1182535