Similar Datasets
Project description:Precise coordination of molecular programs and neuronal growth govern the formation, maintenance, and adaptation of neuronal circuits. RNA metabolism has emerged as a key regulatory node of neural development and nervous system pathologies. To uncover novel cell-type-specific RNA regulators, we systematically investigated expression of RNA recognition motif-containing proteins in the mouse neocortex. Surprisingly, we found RBM20, an alternative splicing regulator associated with dilated cardiomyopathy, to be expressed in cortical parvalbumin interneurons and mitral cells of the olfactory bulb. Genome-wide mapping of RBM20 target mRNAs revealed that neuronal RBM20 binds distal intronic regions. Loss of neuronal RBM20 has only modest impact on alternative splice isoforms but results in a significant reduction in an array of mature mRNAs in the neuronal cytoplasm. This phenotype is particularly pronounced for genes with long introns that encode synaptic proteins. We hypothesize that RBM20 ensures fidelity of pre-mRNA splicing by suppressing non-productive splicing events in long neuronal genes. This work highlights a common requirement of two excitable cell types, cardiomyocytes and neurons, for RBM20-dependent transcriptome regulation.
2023-12-16 | GSE250098 | GEO
Project description:Precise coordination of molecular programs and neuronal growth govern the formation, maintenance, and adaptation of neuronal circuits. RNA metabolism has emerged as a key regulatory node of neural development and nervous system pathologies. To uncover novel cell-type-specific RNA regulators, we systematically investigated expression of RNA recognition motif-containing proteins in the mouse neocortex. Surprisingly, we found RBM20, an alternative splicing regulator associated with dilated cardiomyopathy, to be expressed in cortical parvalbumin interneurons and mitral cells of the olfactory bulb. Genome-wide mapping of RBM20 target mRNAs revealed that neuronal RBM20 binds distal intronic regions. Loss of neuronal RBM20 has only modest impact on alternative splice isoforms but results in a significant reduction in an array of mature mRNAs in the neuronal cytoplasm. This phenotype is particularly pronounced for genes with long introns that encode synaptic proteins. We hypothesize that RBM20 ensures fidelity of pre-mRNA splicing by suppressing non-productive splicing events in long neuronal genes. This work highlights a common requirement of two excitable cell types, cardiomyocytes and neurons, for RBM20-dependent transcriptome regulation.
2023-12-16 | GSE250096 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-08-16 | GSE241120 | GEO
Project description:To elucidate the role of cardiac myosin-binding protein-C (MyBP-C) in myocardial structure and function, we have produced mice expressing altered forms of this sarcomere protein. The engineered mutations encode truncated forms of MyBP-C in which the cardiac myosin heavy chain-binding and titin-binding domain has been replaced with novel amino acid residues. Analogous heterozygous defects in humans cause hypertrophic cardiomyopathy. Mice that are homozygous for the mutated MyBP-C alleles express less than 10% of truncated protein in M-bands of otherwise normal sarcomeres. Homozygous mice bearing mutated MyBP-C alleles are viable but exhibit neonatal onset of a progressive dilated cardiomyopathy with prominent histopathology of myocyte hypertrophy, myofibrillar disarray, fibrosis, and dystrophic calcification. Echocardiography of homozygous mutant mice showed left ventricular dilation and reduced contractile function at birth; myocardial hypertrophy increased as the animals matured. Left-ventricular pressure-volume analyses in adult homozygous mutant mice demonstrated depressed systolic contractility with diastolic dysfunction. These data revise our understanding of the role that MyBP-C plays in myofibrillogenesis during cardiac development and indicate the importance of this protein for long-term sarcomere function and normal cardiac morphology. We also propose that mice bearing homozygous familial hypertrophic cardiomyopathy-causing mutations may provide useful tools for predicting the severity of disease that these mutations will cause in humans.
| S-EPMC409819 | biostudies-literature
Project description:Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by ventricular dilatation and impaired systolic function. Patients with DCM suffer from heart failure, arrhythmia, and are at risk of premature death. DCM has a prevalence of one case out of 2500 individuals with an incidence of 7/100,000/year (but may be under diagnosed). In many cases the disease is inherited and is termed familial DCM (FDC). FDC may account for 20-48% of DCM. FDC is principally caused by genetic mutations in FDC genes that encode for cytoskeletal and sarcomeric proteins in the cardiac myocyte. Family history analysis is an important tool for identifying families affected by FDC. Standard criteria for evaluating FDC families have been published and the use of such criteria is increasing. Clinical genetic testing has been developed for some FDC genes and will be increasingly utilized for evaluating FDC families. Through the use of family screening by pedigree analysis and/or genetic testing, it is possible to identify patients at earlier, or even presymptomatic stages of their disease. This presents an opportunity to invoke lifestyle changes and to provide pharmacological therapy earlier in the course of disease. Genetic counseling is used to identify additional asymptomatic family members who are at risk of developing symptoms, allowing for regular screening of these individuals. The management of FDC focuses on limiting the progression of heart failure and controlling arrhythmia, and is based on currently accepted treatment guidelines for DCM. It includes general measures (salt and fluid restriction, treatment of hypertension, limitation of alcohol intake, control of body weight, moderate exercise) and pharmacotherapy. Cardiac resynchronization, implantable cardioverter defibrillators and left ventricular assist devices have progressively expanding usage. Patients with severe heart failure, severe reduction of the functional capacity and depressed left ventricular ejection fraction have a low survival rate and may require heart transplant.
| S-EPMC1559590 | biostudies-literature
Project description:Protein arginylation mediated by arginyltransferase (ATE1) is essential for heart formation during embryogenesis, however its cell-autonomous role in cardiomyocytes and the differentiated heart muscle has never been investigated. To address this question, we generated cardiac muscle-specific Ate1 knockout mice, in which Ate1 deletion was driven by ?-myosin heavy chain promoter (?MHC-Ate1 mouse). These mice were initially viable, but developed severe cardiac contractility defects, dilated cardiomyopathy, and thrombosis over time, resulting in high rates of lethality after 6months of age. These symptoms were accompanied by severe ultrastructural defects in cardiac myofibrils, seen in the newborns and far preceding the onset of cardiomyopathy, suggesting that these defects were primary and likely underlay the development of the future heart defects. Several major sarcomeric proteins were arginylated in vivo. Moreover, Ate1 deletion in the hearts resulted in a significant reduction of active and passive myofibril forces, suggesting that arginylation is critical for both myofibril structural integrity and contractility. Thus, arginylation is essential for maintaining the heart function by regulation of the major myofibril proteins and myofibril forces, and its absence in the heart muscle leads to progressive heart failure through cardiomyocyte-specific defects.
| S-EPMC3418387 | biostudies-literature
Project description:Peripartum cardiomyopathy (PPCM) is a severe cardiac disease occurring in the last month of pregnancy or in the first 5 months after delivery and shows many similar clinical characteristics as dilated cardiomyopathy (DCM) such as ventricle dilation and systolic dysfunction. While PPCM was believed to be DCM triggered by pregnancy, more and more studies show important differences between these diseases. While it is likely they share part of their pathogenesis such as increased oxidative stress and an impaired microvasculature, discrepancies seen in disease progression and outcome indicate there must be differences in pathogenesis as well. In this review, we compared studies in DCM and PPCM to search for overlapping and deviating disease etiology, pathogenesis and outcome in order to understand why these cardiomyopathies share similar clinical features but have different underlying pathologies.
| S-EPMC4295435 | biostudies-other
Project description:Cardiac ?-myosin variants cause hypertrophic (HCM) or dilated (DCM) cardiomyopathy by disrupting sarcomere contraction and relaxation. The locations of variants on isolated myosin head structures predict contractility effects but not the prominent relaxation and energetic deficits that characterize HCM. During relaxation, pairs of myosins form interacting-heads motif (IHM) structures that with other sarcomere proteins establish an energy-saving, super-relaxed (SRX) state. Using a human ?-cardiac myosin IHM quasi-atomic model, we defined interactions sites between adjacent myosin heads and associated protein partners, and then analyzed rare variants from 6112 HCM and 1315 DCM patients and 33,370 ExAC controls. HCM variants, 72% that changed electrostatic charges, disproportionately altered IHM interaction residues (expected 23%; HCM 54%, p=2.6×10-19; DCM 26%, p=0.66; controls 20%, p=0.23). HCM variant locations predict impaired IHM formation and stability, and attenuation of the SRX state - accounting for altered contractility, reduced diastolic relaxation, and increased energy consumption, that fully characterizes HCM pathogenesis.
| S-EPMC5469618 | biostudies-literature
Project description:We sought to identify a novel gene for dilated cardiomyopathy (DCM).DCM is a heritable, genetically heterogeneous disorder that remains idiopathic in the majority of patients. Familial cases provide an opportunity to discover unsuspected molecular bases of DCM, enabling pre-clinical risk detection.Two large families with autosomal-dominant DCM were studied. Genome-wide linkage analysis was used to identify a disease locus, followed by fine mapping and positional candidate gene sequencing. Mutation scanning was then performed in 278 unrelated subjects with idiopathic DCM, prospectively identified at the Mayo Clinic.Overlapping loci for DCM were independently mapped to chromosome 10q25-q26. Deoxyribonucleic acid sequencing of affected individuals in each family revealed distinct heterozygous missense mutations in exon 9 of RBM20, encoding ribonucleic acid (RNA) binding motif protein 20. Comprehensive coding sequence analyses identified missense mutations clustered within this same exon in 6 additional DCM families. Mutations segregated with DCM (peak composite logarithm of the odds score >11.49), were absent in 480 control samples, and altered residues within a highly conserved arginine/serine (RS)-rich region. Expression of RBM20 messenger RNA was confirmed in human heart tissue.Our findings establish RBM20 as a DCM gene and reveal a mutation hotspot in the RS domain. RBM20 is preferentially expressed in the heart and encodes motifs prototypical of spliceosome proteins that regulate alternative pre-messenger RNA splicing, thus implicating a functionally distinct gene in human cardiomyopathy. RBM20 mutations are associated with young age at diagnosis, end-stage heart failure, and high mortality.
| S-EPMC2782634 | biostudies-literature
Project description:Our understanding of heart failure (HF) has been provided by indirect surrogates, such as post-mortem histology, cardiovascular imaging, and molecular characterisation in vivo and in vitro, rather than directly in pre-mortem human cardiac tissue. Using our heart bank of pre-mortem hearts procured according to the most stringent protocols, we examined ischemic (ICM) and dilated cardiomyopathy (DCM) -- the most common causes of HF and leading causes of cardiac transplantation1. We performed unbiased, comprehensive, paired proteomic and metabolomic analysis of 51 left ventricular (LV) samples from 44 cryopreserved pre-mortem human ICM and DCM hearts, including age-matched, healthy, histopathologically-normal donor controls of both genders for comparison. Data integration via pathway and correlation network analysis revealed overlapping and divergent disease pathways in ICM and DCM, and, strikingly, precise sex-specific differences within each disease that unveil the interaction of gender with HF. Identified core functional nodes in each disease may serve as novel therapeutic targets, and we provide all proteomic and metabolomic results via an interactive online repository (https://mengboli.shinyapps.io/heartomics/) as a publicly available resource.
2020-05-01 | PXD018678 | Pride