A heterozygous variant in the human cardiac miR-133 gene, MIR133A2, alters miRNA duplex processing and strand abundance

BACKGROUND MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Sequential cleavage of miRNA precursors results in a ~22 nucleotide duplex of which one strand, the mature miRNA, is typically loaded into the RNA-induced silencing complex (RISC) while the passenger strand is degraded. Very little is known about how genetic variation might affect miRNA biogenesis and function. RESULTS We re-sequenced the MIR1-1, MIR1-2, MIR133A1, MIR133A2, and MIR133B genes, that encode the cardiac-enriched miRNAs, miR-1 and miR-133, in 120 individuals with familial atrial fibrillation and identified 10 variants, including a novel 79T > C MIR133A2 substitution. This variant lies within the duplex at the 3' end of the mature strand, miR-133a-3p, and is predicted to prevent base-pairing and weaken thermostability at this site, favoring incorporation of the passenger strand, miR-133a-5p, into RISC. Genomic DNA fragments containing miR-133a-2 precursor sequences with 79T and 79C alleles were transfected into HeLa cells. On Northern blotting the 79T allele showed strong expression of miR-133a-3p with weak expression of miR-133a-5p. In contrast, the 79C allele had no effect on miR-133a-3p but there was a significant increase (mean 3.6-fold) in miR-133a-5p levels. Deep sequencing of small RNA libraries prepared from normal human and murine atria confirmed that nearly all the mature miR-133a was comprised of miR-133a-3p and that levels of miR-133a-5p were very low. A number of isomiRs with variations at 5' and 3' ends were identified for both miR-133a-3p and miR-133a-5p, with 2 predominant miR-133a-3p isomiRs and one predominant miR-133a-5p isomiR. Bioinformatics analyses indicate that the major miR-133a-3p and 5p isomiRs have numerous predicted target mRNAs, only a few of which are in common. CONCLUSIONS Multiple miR-133a isomiRs with potential different mRNA target profiles are present in the atrium in humans and mice. We identified a human 79T > C MIR133A2 variant that alters miRNA processing and results in accumulation of the miR-133a-5p strand that is usually degraded

Investigating the role of sensitive industries and ESG performance in enhancing Corporate Financial Performance : empirical analysis from the United States

This study explores the correlation between ESG performance and financial performance in US corporations. It examines the relationship between overall ESG performance and specific components (environmental, social, and governance). Financial indicators like Tobin's Q, ROA, and ROE are analyzed. Additionally, the study investigates the connection between industry sensitivity and ESG scores. An analysis based on recent data extracted from Compustat and Thomson Reuters databases of a time period of 6 years from 2016 to 2021 has been carried out. Data from a total of 2759 companies, both in the sensitive and non-sensitive sectors, were analyzed using multivariate regressions. Tobin's Q results demonstrate a positive relationship between ESG score, Environmental Score, Social Score, Governance Score, and Corporate Financial Performance. However, the results using the ROA measure do not align with previous studies, and the low coefficient prevents any conclusive evidence on the relationship with Corporate Financial Performance. Regarding ROE, the results are mixed. No significant relationship was found between ESG score and Governance score with ROE. However, the Environmental Score shows a significant positive relationship with ROE, while the Social score suggests a potential positive relationship. Furthermore, statistically significant positive relationships were observed between being in a sensitive industry and the ESG score, Social score, and Governance score. However, no clear association was found between industry sensitivity and the Environmental score.Este estudo explora a correlação entre o desempenho ESG e o desempenho financeiro em corporações dos Estados Unidos. Ele examina a relação entre o desempenho ESG geral e seus componentes específicos (ambiental, social e governança). Indicadores financeiros como Tobin's Q, ROA e ROE são analisados. Além disso, o estudo investiga a conexão entre a sensibilidade da indústria e as pontuações ESG. Foi realizada uma análise com base em dados recentes de 2759 empresas, em um período de 6 anos, de 2016 a 2021. Os resultados do Tobin's Q mostram uma relação positiva entre a pontuação ESG, a pontuação Ambiental, a pontuação Social, a pontuação de Governança e o Desempenho Financeiro Corporativo. No entanto, os resultados utilizando ROA não são conclusivos sobre a relação com o Desempenho Financeiro Corporativo. Em relação ao ROE, os resultados são mistos. Não foi encontrada nenhuma relação significativa entre a pontuação ESG e a pontuação de Governança com o ROE. No entanto, a pontuação Ambiental apresenta uma relação positiva significativa com o ROE, enquanto a pontuação Social sugere uma possível relação positiva. Além disso, foram observadas relações positivas estatisticamente significativas entre estar em uma indústria sensível e as pontuações ESG, Social e Governança. Porém, não foi encontrada uma associação clara entre a sensibilidade da indústria e a pontuação Ambiental

Irreversible triggers for hypertrophic cardiomyopathy are established in the early postnatal period

Background: Hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein genes, and left ventricular hypertrophy (LVH) develops as an adaptive response to sarcomere dysfunction. It remains unclear whether persistent expression of the mutant gene is required for LVH or whether early gene expression acts as an immutable inductive trigger. Objectives: The aim of this study was to use a regulatable murine model of HCM to study the reversibility of pathological LVH. Methods: The authors generated a double-transgenic mouse model, tTA x αMHC R403Q , in which expression of the HCM-causing Arg403Gln mutation in the α-myosin heavy chain (MHC) gene is inhibited by doxycycline administration. Cardiac structure and function were evaluated in groups of mice that received doxycycline for varying periods from 0 to 40 weeks of age. Results: Untreated tTA x αMHC R403Q mice showed increased left ventricular (LV) mass, contractile dysfunction, myofibrillar disarray, and fibrosis. In contrast, mice treated with doxycycline from conception to 6 weeks had markedly less LVH and fibrosis at 40 weeks. Transgene inhibition from 6 weeks reduced fibrosis but did not prevent LVH or functional changes. There were no differences in LV parameters at 40 weeks between mice with transgene inhibition from 20 weeks and mice with continuous transgene expression. Conclusions: These findings highlight the critical role of the early postnatal period in HCM pathogenesis and suggest that mutant sarcomeres manifest irreversible cardiomyocyte defects that induce LVH. In HCM, mutation-silencing therapies are likely to be ineffective for hypertrophy regression and would have to be administered very early in life to prevent hypertrophy development

DMD-associated dilated cardiomyopathy : genotypes, phenotypes, and phenocopies

Background: Variants in the DMD gene, that encodes the cytoskeletal protein, dystrophin, cause a severe form of dilated cardiomyopathy (DCM) associated with high rates of heart failure, heart transplantation, and ventricular arrhythmias. Improved early detection of individuals at risk is needed. Methods: Genetic testing of 40 male probands with a potential X-linked genetic cause of primary DCM was undertaken using multi-gene panel sequencing, multiplex polymerase chain reaction, and array comparative genomic hybridization. Variant location was assessed with respect to dystrophin isoform patterns and exon usage. Telomere length was evaluated as a marker of myocardial dysfunction in left ventricular tissue and blood. Results: Four pathogenic/likely pathogenic DMD variants were found in 5 probands (5/40: 12.5%). Only one rare variant was identified by gene panel testing with 3 additional multi-exon deletion/duplications found following targeted assays for structural variants. All of the pathogenic/likely pathogenic DMD variants involved dystrophin exons that had percent spliced-in scores >90, indicating high levels of constitutive expression in the human adult heart. Fifteen DMD variant-negative probands (15/40: 37.5%) had variants in autosomal genes including TTN, BAG3, LMNA, and RBM20. Myocardial telomere length was reduced in patients with DCM irrespective of genotype. No differences in blood telomere length were observed between genotype-positive family members with/without DCM and controls. Conclusions: Primary genetic testing using multi-gene panels has a low yield and specific assays for structural variants are required if DMD-associated cardiomyopathy is suspected. Distinguishing X-linked causes of DCM from autosomal genes that show sex differences in clinical presentation is crucial for informed family management. © 2023 American Heart Association, Inc

Conserved Role of the Large Conductance Calcium-Activated Potassium Channel, KCa1.1, in Sinus Node Function and Arrhythmia Risk

BACKGROUND: KCNMA1 encodes the α-subunit of the large-conductance Ca(2+)-activated K(+) channel, K(Ca)1.1, and lies within a linkage interval for atrial fibrillation (AF). Insights into the cardiac functions of K(Ca)1.1 are limited, and KCNMA1 has not been investigated as an AF candidate gene. METHODS: The KCNMA1 gene was sequenced in 118 patients with familial AF. The role of K(Ca)1.1 in normal cardiac structure and function was evaluated in humans, mice, zebrafish, and fly. A novel KCNMA1 variant was functionally characterized. RESULTS: A complex KCNMA1 variant was identified in 1 kindred with AF. To evaluate potential disease mechanisms, we first evaluated the distribution of K(Ca)1.1 in normal hearts using immunostaining and immunogold electron microscopy. K(Ca)1.1 was seen throughout the atria and ventricles in humans and mice, with strong expression in the sinus node. In an ex vivo murine sinoatrial node preparation, addition of the K(Ca)1.1 antagonist, paxilline, blunted the increase in beating rate induced by adrenergic receptor stimulation. Knockdown of the K(Ca)1.1 ortholog, kcnma1b, in zebrafish embryos resulted in sinus bradycardia with dilatation and reduced contraction of the atrium and ventricle. Genetic inactivation of the Drosophila K(Ca)1.1 ortholog, slo, systemically or in adult stages, also slowed the heartbeat and produced fibrillatory cardiac contractions. Electrophysiological characterization of slo-deficient flies revealed bursts of action potentials, reflecting increased events of fibrillatory arrhythmias. Flies with cardiac-specific overexpression of the human KCNMA1 mutant also showed increased heart period and bursts of action potentials, similar to the K(Ca)1.1 loss-of-function models. CONCLUSIONS: Our data point to a highly conserved role of K(Ca)1.1 in sinus node function in humans, mice, zebrafish, and fly and suggest that K(Ca)1.1 loss of function may predispose to AF