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

Jordà, Paloma; Toro, Rocío; Díez, Crisanto; Salazar-Mendiguchía, Joel; Fernández-Falgueras, Anna; Pérez‐Serra, Alexandra; Coll, Mónica; Puigmulé, Marta; Arbelo, Elena; García‐Álvarez, Ana; Sarquella-Brugada, Geòrgia; César, Sergi; Tirón, Coloma; Iglesias, Anna; Brugada, Josép; Brugada, Ramón; Campuzano, Òscar

doi:10.3390/jpm11020130

Cited by 5 publications

(4 citation statements)

References 75 publications

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“…These hot phases may also occur in patients with LP/P variants in filamin-C, lamin A/C, and RNA-binding motif-20. 78,79 These genes are all known to be pro-arrhythmogenic, similar to the classical desmosomal ACM genes. Whether this inflammatory response drives the disease process or is rather reflecting a reparative process along with cardiomyocyte suffering or necrosis in these highly penetrant gene LP/P variants is yet unclear.…”

Section: Genetic Susceptibility In Myocarditismentioning

confidence: 99%

Clinical Characteristics and Mechanisms of Acute Myocarditis

Heymans,

Van Linthout,

Kraus

et al. 2024

Circulation Research

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Myocarditis is defined by an immune response to infection or injury, most commonly identified after a viral infection or recent exposure to cardiotoxins or drugs. Classic myocarditis may also result from the activation of the immune system by self-antigens without an exogenous trigger. Pathogenic variants of genes encoding sarcolemmal and desmosomal proteins are present in 4% to 44% of myocarditis patients and may relate to persistent cardiac dysfunction and arrhythmias. The most common clinical presentation is acute chest pain resembling an ischemic infarction or pericarditis. Heart failure and syncope from tachy- or brady-arrhythmias are features of a complicated clinical course with substantial risk of future cardiovascular events and death. High-sensitivity troponin, ECG, and echocardiograms are useful but lack sufficient sensitivity and specificity to confirm the diagnosis. Cardiovascular magnetic resonance is indicated to confirm myocarditis in low-risk, uncomplicated cases. Endomyocardial biopsy is indicated to guide therapy in high-risk scenarios. In this review, we discuss the clinical aspects, pathogenesis, genetic susceptibility, and management of uncomplicated, complicated, and fulminant myocarditis related to viral injury. We identify gaps in understanding and suggest prime research questions in the pathogenesis, diagnosis, and treatment of acute myocarditis. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05335928.

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Section: Genetic Susceptibility In Myocarditismentioning

confidence: 99%

Clinical Characteristics and Mechanisms of Acute Myocarditis

Heymans,

Van Linthout,

Kraus

et al. 2024

Circulation Research

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“…Since these first patients with RBM20 variants [7], several dozen variants have been reported so far [8], most of which were associated with DCM phenotypes.…”

Section: Introductionmentioning

confidence: 99%

“…The mutation hotspot region of RBM20 is within the RS domain [8,13], among which P633L, R634Q, R634W, R634L, S635A, R636S, R636C, R636H, S637G, and P638L are within the RSRSP stretch. In contrast, few RBM20 disease variants have been found within the RNA-recognition motif (RRM) domain.…”

Section: Introductionmentioning

confidence: 99%

I536T variant of RBM20 affects splicing of cardiac structural proteins that are causative for developing dilated cardiomyopathy

et al. 2022

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RBM20 is one of the genes predisposing to dilated cardiomyopathy (DCM). Variants in the RS domain have been reported in many DCM patients, but the pathogenicity of variants within the RNA-recognition motif remains unknown. Two human patients with the I536T-RBM20 variant without an apparent DCM phenotype were identified in sudden death cohorts. A splicing reporter assay was performed, and an I538T knock-in mouse model (Rbm20I538T) was generated to determine the significance of this variant. The reporter assay demonstrated that the human I536T variant affected the TTN splicing pattern compared to wild-type. In the mouse experiments, Rbm20I538T mice showed different splicing patterns in Ttn, Ldb3, Camk2d, and Ryr2. The expressions of Casq1, Mybpc2, and Myot were upregulated in Rbm20I538T mice, but Rbm20I538T mice showed neither DCM nor cardiac dysfunction on histopathological examination and ultrasound echocardiography. The I536T-RBM20 (I538T-Rbm20) variant changes gene splicing and affects gene expression, but the splicing and expression changes in Ttn and Ca handling genes such as Casq1, Camk2d, and Ryr2 do not cause DCM morphology in the mouse model. Key messages • Two human patients with the I536T-RBM20 variant without a DCM phenotype were identified. • A splicing reporter assay demonstrated that the variant affected the TTN splicing. • Rbm20I538T mice showed neither DCM nor cardiac dysfunction. • Rbm20I538T mice showed different splicing patterns and the gene expressions.

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“…Other cardiomyopathy associated mutations were found in the Glu-rich region of the protein [10,16]. Although there are several reports of nonsense or frameshift variants in RBM20 associated with DCM or left ventricular non-compaction cardiomyopathy (LVNC), the pathomechanism of these mutations remains unclear [17][18][19][20][21][22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

The Combined Human Genotype of Truncating TTN and RBM20 Mutations Is Associated with Severe and Early Onset of Dilated Cardiomyopathy

Gärtner

Bloebaum

Brodehl

et al. 2021

Genes

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A major cause of heart failure is cardiomyopathies, with dilated cardiomyopathy (DCM) as the most common form. Over 40 genes are linked to DCM, among them TTN and RBM20. Next Generation Sequencing in clinical DCM cohorts revealed truncating variants in TTN (TTNtv), accounting for up to 25% of familial DCM cases. Mutations in the cardiac splicing factor RNA binding motif protein 20 (RBM20) are also known to be associated with severe cardiomyopathies. TTN is one of the major RBM20 splicing targets. Most of the pathogenic RBM20 mutations are localized in the highly conserved arginine serine rich domain (RS), leading to a cytoplasmic mislocalization of mutant RBM20. Here, we present a patient with an early onset DCM carrying a combination of (likely) pathogenic TTN and RBM20 mutations. We show that the splicing of RBM20 target genes is affected in the mutation carrier. Furthermore, we reveal RBM20 haploinsufficiency presumably caused by the frameshift mutation in RBM20.

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

Cited by 5 publications

References 75 publications

Clinical Characteristics and Mechanisms of Acute Myocarditis

Clinical Characteristics and Mechanisms of Acute Myocarditis

I536T variant of RBM20 affects splicing of cardiac structural proteins that are causative for developing dilated cardiomyopathy

The Combined Human Genotype of Truncating TTN and RBM20 Mutations Is Associated with Severe and Early Onset of Dilated Cardiomyopathy

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