iPSC Modeling of RBM20-Deficient DCM Identifies Upregulation of RBM20 as a Therapeutic Strategy

Briganti, Francesca; Sun, Han; Wu, Wei; Wu, Jingyan; Zhu, Chenchen; Liss, Martin; Karakikes, Ioannis; Rego, Shannon; Cipriano, Andrea; Snyder, M; Meder, Benjamin; Xu, Zhenyu; Millat, Gilles; Gotthardt, Michael; Mercola, Mark; Steinmetz, Lars M.

doi:10.1016/j.celrep.2020.108117

Cited by 40 publications

(65 citation statements)

References 58 publications

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“…In the first amino acid of this hot-spot, only one rare variant has been recently reported-p.(Pro633Leu). Clinical, genetic, and functional studies confirmed the pathogenic role of this rare variant [55]. Importantly, in this recent study, the authors also suggested that the upregulation of RBM20 may be a viable therapeutic strategy for RBM20-related DCM.…”

Section: Rare Rbm20 Variants In Familial Dilated Cardiomyopathysupporting

confidence: 57%

Malignant Arrhythmogenic Role Associated with RBM20: A Comprehensive Interpretation Focused on a Personalized Approach

Jordà

Toro

Díez

et al. 2021

JPM

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The RBM20 gene encodes the muscle-specific splicing factor RNA-binding motif 20, a regulator of heart-specific alternative splicing. Nearly 40 potentially deleterious variants in RBM20 have been reported in the last ten years, being found to be associated with highly arrhythmogenic events in familial dilated cardiomyopathy. Frequently, malignant arrhythmias can be a primary manifestation of disease. The early recognition of arrhythmic genotypes is crucial in avoiding lethal episodes, as it may have an impact on the adoption of personalized preventive measures. Our study performs a comprehensive update of data concerning rare variants in RBM20 that are associated with malignant arrhythmogenic phenotypes with a focus on personalized medicine.

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Section: Rare Rbm20 Variants In Familial Dilated Cardiomyopathysupporting

confidence: 57%

Malignant Arrhythmogenic Role Associated with RBM20: A Comprehensive Interpretation Focused on a Personalized Approach

Jordà

Toro

Díez

et al. 2021

JPM

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“…To investigate the benefits of ARRY-371797 in DCM patients with LMNA mutations, patients with LMNA mutations, a clinical trial is currently ongoing to evaluate its effectiveness based on changes in the 6 min-walk tests over a 24 weeks-time period (NCT03439514). With the increasing focus on the role of RBM20 as a master regulator of alternative splicing, recent data suggest that in patients with reduced RBM20 activity, all-trans retinoic acid (ATRA) could be used to restore RBM20 levels and efficiently curb down the deleterious effects of loss of function mutations in this gene (81).…”

Section: Novel Drugsmentioning

confidence: 99%

The Genetic Pathways Underlying Immunotherapy in Dilated Cardiomyopathy

Kadhi

Mohammed

Nemer

2021

Front. Cardiovasc. Med.

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Heart failure (HF) is a global public health threat affecting 26 million individuals worldwide with an estimated prevalence increase of 46% by 2030. One of the main causes of HF and sudden death in children and adult is Dilated Cardiomyopathy (DCM). DCM is characterized by dilation and systolic dysfunction of one or both ventricles. It has an underlying genetic basis or can develop subsequent to various etiologies that cause myocardium inflammation (secondary causes). The morbidity and mortality rates of DCM remains high despite recent advancement to manage the disease. New insights have been dedicated to better understand the pathogenesis of DCM in respect to genetic and inflammatory basis by linking the two entities together. This cognizance in the field of cardiology might have an innovative approach to manage DCM through targeted treatment directed to the causative etiology. The following review summarizes the genetical and inflammatory causes underlying DCM and the pathways of the novel precision-medicine-based immunomodulatory strategies to salvage and prevent the associated heart failure linked to the disease.

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“…Following these seminal findings that delineated the role of RBM20 driven splicing in titin isoforms, the ribonucleoprotein RBM20 has now paralled the role of titin in regulating structural and functional characteristics of cardiac development and disease. Cardiac-specific splicing events are attributed to RBM20, and recent studies with defective RBM20 variants have been shown to be associated with cardiac transcript variants resulting in cardiomyopathy including DCM (dilated cardiomyopathy) [180][181][182][183][184][185][186][187][188][189][190].…”

Section: Rbm20 Interactome In Cardiac Development and Disease: Determmentioning

confidence: 99%

The Cellular Stress Response Interactome and Extracellular Matrix Cross-Talk during Fibrosis: A Stressed Extra-Matrix Affair

Sharma¹,

Kaushal²,

Rawat³

et al. 2021

Extracellular Matrix - Developments and Therapeutics

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Diverse internal and external pathologic stimuli can trigger cellular stress response pathways (CSRPs) that are usually counteracted by intrinsic homeostatic machinery, which responds to stress by initiating complex signaling mechanisms to eliminate either the stressor or the damaged cells. There is growing evidence that CSRPs can have context-dependent homeostatic or pathologic functions that may result in tissue fibrosis under persistence of stress. CSRPs can drive intercellular communications through exosomes (trafficking and secretory pathway determinants) secreted in response to stress-induced proteostasis rebalancing. The injured tissue environment upon sensing the stress turns on a precisely orchestrated network of immune responses by regulating cytokine-chemokine production, recruitment of immune cells, and modulating fibrogenic niche and extracellular matrix (ECM) cross-talk during fibrotic pathologies like cardiac fibrosis, liver fibrosis, laryngotracheal stenosis, systemic scleroderma, interstitial lung disease and inflammatory bowel disease. Immunostimulatory RNAs (like double stranded RNAs) generated through deregulated RNA processing pathways along with RNA binding proteins (RBPs) of RNA helicase (RNA sensors) family are emerging as important components of immune response pathways during sterile inflammation. The paradigm-shift in RNA metabolism associated interactome has begun to offer new therapeutic windows by unravelling the novel RBPs and splicing factors in context of developmental and fibrotic pathways. We would like to review emerging regulatory nodes and their interaction with CSRPs, and tissue remodeling with major focus on cardiac fibrosis, and inflammatory responses underlying upper airway fibrosis.

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iPSC Modeling of RBM20-Deficient DCM Identifies Upregulation of RBM20 as a Therapeutic Strategy

Cited by 40 publications

References 58 publications

Malignant Arrhythmogenic Role Associated with RBM20: A Comprehensive Interpretation Focused on a Personalized Approach

Malignant Arrhythmogenic Role Associated with RBM20: A Comprehensive Interpretation Focused on a Personalized Approach

The Genetic Pathways Underlying Immunotherapy in Dilated Cardiomyopathy

The Cellular Stress Response Interactome and Extracellular Matrix Cross-Talk during Fibrosis: A Stressed Extra-Matrix Affair

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