RBM20-Related Cardiomyopathy: Current Understanding and Future Options

Koelemen, Jan; Gotthardt, Michael; Steinmetz, Lars M.; Meder, Benjamin

doi:10.3390/jcm10184101

Cited by 24 publications

(12 citation statements)

References 67 publications

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“…In addition, a mutation in the glutamate-rich region of RBM20 causes DCM through missplicing of titin and impaired Frank–Starling mechanism ( 55 ). More descriptions of the relationship between RBM20 variation and corresponding exons and pathogenicity were summarized in previous reviews ( 61 ). Subendocardial fibrosis accompanied by electrical abnormalities has been observed in RBM20-null heterozygous or homozygous rats ( 58 ).…”

Section: Splicing Factors Play An Essential Role In Modulating Titin ...mentioning

confidence: 99%

RBM20, a Therapeutic Target to Alleviate Myocardial Stiffness via Titin Isoforms Switching in HFpEF

Hang

Shu

et al. 2022

Front. Cardiovasc. Med.

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Increased myocardial stiffness is critically involved in heart diseases with impaired cardiac compliance, especially heart failure with preserved ejection fraction (HFpEF). Myocardial stiffness mainly derives from cardiomyocyte- and extracellular matrix (ECM)-derived passive stiffness. Titin, a major component of sarcomeres, participates in myocardial passive stiffness and stress-sensitive signaling. The ratio of two titin isoforms, N2BA to N2B, was validated to influence diastolic dysfunction via several pathways. RNA binding motif protein 20 (RBM20) is a well-studied splicing factor of titin, functional deficiency of RBM20 in mice profile improved cardiac compliance and function, which indicated that RBM20 functions as a potential therapeutic target for mitigating myocardial stiffness by modulating titin isoforms. This minor review summarized how RBM20 and other splicing factors modify the titin isoforms ratio, therefore providing a promising target for improving the myocardial compliance of HFpEF.

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Section: Splicing Factors Play An Essential Role In Modulating Titin ...mentioning

confidence: 99%

RBM20, a Therapeutic Target to Alleviate Myocardial Stiffness via Titin Isoforms Switching in HFpEF

Hang

Shu

et al. 2022

Front. Cardiovasc. Med.

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“…Loss of function mutations leads to missplicing of these proteins. Affected patients present with an early-onset and fastly-progressing disease with severe heart failure, high arrhythmic burden and SCD [33,34].…”

Section: Non-desmosomal Abnormalities In Acmmentioning

confidence: 99%

The Challenges of Diagnosis and Treatment of Arrhythmogenic Cardiomyopathy: Are We there yet?

Spadotto¹,

Morabito²,

Carecci³

et al. 2022

Rev. Cardiovasc. Med.

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Background: we sought to review the evolution in the diagnosis and treatment of Arrhythmogenic Cardiomyopathy (ACM), a clinically multifaceted entity beyond the observation of ventricular arrhythmias, and the outcome of therapies aiming at sudden death prevention in a single center experience. Methods: retrospective analysis of the data of consecutive patients with an implanted cardioverter-defibrillator (ICD) and a confirmed diagnosis of ACM according to the proposed Padua Criteria, who were referred to our center from January 1992 to October 2021. Results: we enrolled 72 patients (66% males, mean age at implant 46 ± 16 years), 63.9% implanted for primary prevention. At the time of ICD implant, 29 (40.3%) patients had a right ventricular involvement, 24 (33.3%) had a dominant LV involvement and 19 (26.4%) had a biventricular involvement. After a median follow-up of 6,1 years [IQR: 2.5-9.9], 34 patients (47.2%) had 919 sustained episodes of ventricular arrhythmias (VA). 27 patients (37.5%) had 314 episodes of life-threatening arrhythmias (LT-VA), defined as sustained ventricular tachycardia ≥200 beats/min. Considering only the patients with an ICD capable of delivering ATP, 80.4% of VA and 65% of LT-VA were successfully terminated with ATP. 16 (22.2%) patients had an inappropriate ICD activation, mostly caused by atrial fibrillation, while in 9 patients (12.5%) there was a complication needing reintervention (in 3 cases there was a loss of ventricular sensing dictating lead revision). During the follow-up 11 (15.3%) patients died, most of them due to heart failure, and 8 (11.1%) underwent heart transplantation. Conclusions: ACM is increasingly diagnosed owing to heightened suspicion at ECG examination and to improved imaging technology and availability, though the diagnostic workflow is particularly challenging in the earliest disease stages. ICD therapy is the cornerstone of sudden death prevention, albeit its efficacy is not based on controlled studies, and VT ablation/medical therapy are complementary to this strategy. The high burden of ATP-terminated VA makes shock-only devices debatable. The progressive nature of ACM leads to severe biventricular enlargement and refractory heart failure, which pose significant treatment issues when a predominant RV dysfunction occurs owing to the reduced possibility for mechanical circulatory assistance.

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“…Patients with familial RBM20-DCM normally harbor a single disease-causing variant 18 making it a prime target for base editors to install single nucleotide conversions. RBM20 encodes a cardiac splice factor that regulates alternative splicing of genes critical for the function of cardiomyocytes 18 . RBM20 mutations are enriched in (which was not certified by peer review) is the author/funder.…”

Section: Introductionmentioning

confidence: 99%

“…We focused on mutations in RBM20 , found in 3% of patients with aggressive, early onset DCM. Patients with familial RBM20 -DCM normally harbor a single disease-causing variant 18 making it a prime target for base editors to install single nucleotide conversions. RBM20 encodes a cardiac splice factor that regulates alternative splicing of genes critical for the function of cardiomyocytes 18 .…”

Section: Introductionmentioning

confidence: 99%

“…Patients with familial RBM20-DCM normally harbor a single disease-causing variant 18 making it a prime target for base editors to install single nucleotide conversions. RBM20 encodes a cardiac splice factor that regulates alternative splicing of genes critical for the function of cardiomyocytes 18 . RBM20 mutations are enriched in a small stretch of six amino acids within the RS-domain and were recently shown to result in aberrant formation of cytoplasmic granules, which likely amplify the disease phenotype [19][20][21] .…”

Section: Introductionmentioning

confidence: 99%

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Striated muscle-specific base editing enables correction of mutations causing dilated cardiomyopathy

Grosch

Schraft

Chan

et al. 2022

Preprint

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Dilated cardiomyopathy (DCM) is the second most common cause for heart failure with no cure except a high-risk heart transplantation. Approximately 30% of DCM patients harbor heritable mutations which are amenable to CRISPR-based gene therapy. However, challenges related to delivery of the editing complex and off-target concerns hamper the broad applicability of CRISPR agents in the heart. We employed a combination of the viral gene transfer vector AAVMYO with superior targeting specificity of heart muscle tissue and CRISPR base editors to repair patient mutations in the cardiac splice factor Rbm20, which cause aggressive and arrhythmogenic DCM. Using optimized conditions, we could improve splice defects in human iPSC-derived cardiomyocytes (iPSC-CMs) and repair >70% of cardiomyocytes in two Rbm20 knock-in mouse models that we generated to serve as an in vivo platform of our editing strategy. Treatment of juvenile mice restored the localization defect of RBM20 in 75% of cells and splicing of RBM20 targets including TTN. Three months after injection, cardiac dilation and ejection fraction reached wild-type levels. Single-nuclei RNA sequencing (snRNA-seq) uncovered restoration of the transcriptional profile across all major cardiac cell types and whole-genome sequencing (WGS) revealed no evidence for aberrant off-target editing. Our study highlights the potential of base editors combined with AAVMYO to achieve gene repair for treatment of hereditary cardiac diseases.

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RBM20-Related Cardiomyopathy: Current Understanding and Future Options

Cited by 24 publications

References 67 publications

RBM20, a Therapeutic Target to Alleviate Myocardial Stiffness via Titin Isoforms Switching in HFpEF

RBM20, a Therapeutic Target to Alleviate Myocardial Stiffness via Titin Isoforms Switching in HFpEF

The Challenges of Diagnosis and Treatment of Arrhythmogenic Cardiomyopathy: Are We there yet?

Striated muscle-specific base editing enables correction of mutations causing dilated cardiomyopathy

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