Argelia Medeiros‐Domingo

University Hospital of Zurich

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Syntrophin mutation associated with long QT syndrome through activation of the nNOS–SCN5A macromolecular complex

Proceedings of the National Academy of Sciences (2008)

Kazuo Ueda Carmen R. Valdivia Argelia Medeiros‐Domingo David J. Tester Matteo Vatta

Mutations in 11 genes that encode ion channels or their associated proteins cause inherited long QT syndrome (LQTS) and account for ≈75–80% of cases (LQT1–11). Direct sequencing of SNTA1 , the gene encoding α1-syntrophin, was performed in a cohort of LQTS patients that were negative for mutations in the 11 known LQTS-susceptibility genes. A missense mutation (A390V-SNTA1) was found in a patient with recurrent syncope and markedly prolonged QT interval (QTc, 530 ms). SNTA1 links neuronal nitric oxide synthase (nNOS) to the nNOS inhibitor plasma membrane Ca-ATPase subtype 4b (PMCA4b); SNTA1 also is known to associate with the cardiac sodium channel SCN5A. By using a GST-fusion protein of the C terminus of SCN5A, we showed that WT-SNTA1 interacted with SCN5A, nNOS, and PMCA4b. In contrast, A390V-SNTA1 selectively disrupted association of PMCA4b with this complex and increased direct nitrosylation of SCN5A. A390V-SNTA1 expressed with SCN5A, nNOS, and PMCA4b in heterologous cells increased peak and late sodium current compared with WT-SNTA1, and the increase was partially inhibited by NOS blockers. Expression of A390V-SNTA1 in cardiac myocytes also increased late sodium current. We conclude that the A390V mutation disrupted binding with PMCA4b, released inhibition of nNOS, caused S -nitrosylation of SCN5A, and was associated with increased late sodium current, which is the characteristic biophysical dysfunction for sodium-channel-mediated LQTS (LQT3). These results establish an SNTA1-based nNOS complex attached to SCN5A as a key regulator of sodium current and suggest that SNTA1 be considered a rare LQTS-susceptibility gene.

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10.1073/pnas.0801294105

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Citations (320)

[Electric therapy for heart failure].

PubMed (2003)

Celso Mendoza González Pedro Iturralde Torres Argelia Medeiros‐Domingo

The different means for treating congestive heart failure have not yet achieved the improvement in quality of life and the prognosis of people with terminal stage cardiac disease. Some treatment resources, such as cardiac transplant, are only accessible for a selected group of patients. In the last decade, the interest on the role of electromechanic disturbances has grown and has motivated special interest for the use of the pacemaker as a tool for the treatment of congestive heart failure. During this period we have seen an important progress of this kind of treatment and, nowadays, multicenter studies have shown the hemodynamic improvement of the patients treated with this method. Selection of patients for this kind of treatment should be careful; although today it can be known which patients can benefit from this device in the treatment of congestive heart failure.

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Acute basilar artery occlusion : what the radiologist should know.

L. E. Guerrero Acosta Argelia Medeiros‐Domingo William Escobar S. Rovira E. Salvadó

Poster: ECR 2016 / C-1984 / Acute basilar artery occlusion : what the radiologist should know. by: L. E. Guerrero Acosta 1, A. Domingo2, W. Escobar3, S. Cordoba Rovira1, E. Salvado1; 1Tarragona/ES, 2ELS PALLARESOS/ES, 3Cali/CO

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Myocardial expression profiles of candidate molecules in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia compared to those with dilated cardiomyopathy and healthy controls

Heart Rhythm (2015)

Deniz Akdiş Argelia Medeiros‐Domingo Anna Gaertner Jeannette I. Kast Frank Enseleit

Dilated Cardiomyopathy

Phospholamban

Pathogenesis

10.1016/j.hrthm.2015.11.010

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Citations (32)

Four TRPM4 Cation Channel Mutations Found in Cardiac Conduction Diseases Lead to Altered Protein Stability

Frontiers in Physiology (2018)

Beatrice Bianchi Lijo Cherian Ozhathil Argelia Medeiros‐Domingo Michael H. Gollob Hugues Abriel

Transient receptor potential melastatin member 4 (TRPM4), a non-selective cation channel, mediates cell membrane depolarization in immune response, insulin secretion, neurological disorders, and cancer. Pathological variants in TRPM4 gene have been linked to several cardiac phenotypes such as complete heart block (CHB), ventricular tachycardia, and Brugada syndrome (BrS). Despite recent findings regarding the functional implications of TRPM4 in cardiac diseases, the molecular and cellular mechanisms leading to altered conduction are poorly understood. In the present study, we identify and characterize four novel TRPM4 variants found in patients with CHB or ventricular fibrillation. Three of them, p.A101T, p.S1044C and a double variant p.A101T/P1204L, led to a decreased expression and function of the channel. On the contrary, the variant p.Q854R showed an increase in TRPM4 current. Recent evidence indicates that altered degradation rate of mutant proteins represents a pathogenic mechanism underlying genetic diseases. In consequence, protein turnover of WT-TRPM4 and TRPM4 variants overexpressed in HEK293 cells was analyzed using cycloheximide, an inhibitor of protein biosynthesis. Upon addition of cycloheximide, WT-TRPM4 decayed with a half-life of ~20 h, while loss-of-expression variants showed a ~30% increase in degradation rate, with a half-life close to 12 h. Together, the gain-of-expression variant showed a higher stability and a doubled half-life compared to WT-TRPM4. In conclusion, decreased or increased protein expression of several TRPM4 variants linked to cardiac conduction disorders or ventricular arrhythmias were found to be caused by altered TRPM4 half-life compared to the WT form.

10.3389/fphys.2018.00177

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Citations (45)

Abstract 4400: Comprehensive Open Reading Frame Mutational Analysis of the RYR2- Encoded Ryanodine Receptor/Calcium Channel in Patients Diagnosed Previously with Either Catecholaminergic Polymorphic Ventricular Tachycardia or Genotype Negative, Exercise-Induced Long QT Syndrome

Circulation (2008)

Argelia Medeiros‐Domingo David J. Tester Michael J. Ackerman

Pathogenic mutations in the RYR2 -encoded cardiac ryanodine receptor cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1), a cardiac channelopathy with increased propensity for lethal ventricular dysrhythmias. Most RYR2 mutational analyses target three canonical domains encoded by < 40% of the translated exons. The extent of mutations localizing outside of these domains remains unknown as RYR2 has not been examined comprehensively in most patient cohorts. Mutational analysis of all 105 RYR2 exons was performed using PCR, DHPLC, and DNA sequencing on 108 unrelated patients (57% females, 96% white, age at diagnosis 18 ± 13 years, mean QTc 424 ± 26 ms) with either an explicit referral diagnosis of CPVT (N = 60) or an initial diagnosis of exercise-induced long QT syndrome (LQTS) but with QTc < 480 ms and a subsequent negative LQTS genetic test (N = 48). Two hundred healthy individuals from the Human Genetic Cell Repository were examined to assess allelic frequency for all non-synonymous variants detected. Thirty-eight (15 novel) possible CPVT1-associated mutations absent in 400 reference alleles, were detected in 44 unrelated patients (41%). Three cases (7%) had >1 RYR2 mutation. Besides the 25 exons known previously to contain causative mutations, eight new mutation-containing exons were identified: 10, 12, 13, 21, 26, 40, 42, and 48. Nearly two-thirds of the CPVT1-positive patients had mutations that localized to one of only 7 exons: 8, 14, 47, 90, 93, 100, and 101. In addition, 5 (2 novel) common non-synonymous single nucleotide polymorphisms were identified. This study represents one of the largest cohorts of patients for which RYR2 was examined in its entirety. Possible CPVT1 mutations in RYR2 were identified in approximately 41% of both CPVT referrals and LQTS gene-negative patients with exercise-induced syncope and QTc <480 ms. Including the eight new exons hosting mutations in this study, 33 of the 105 translated exons are now known to host possible mutations. Considering that two-thirds of CPVT1-positive cases would be discovered by selective analysis of <10 exons, a tiered targeting strategy for mutation discovery may afford a more cost-effective approach to CPVT genetic testing.

10.1161/circ.118.suppl_18.s_881-c

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Citations (1)

Reduced desmoplakin immunofluorescence signal in arrhythmogenic cardiomyopathy with epicardial right ventricular outflow tract tachycardia

HeartRhythm Case Reports (2018)

Sabina Rosset Argelia Medeiros‐Domingo Angeliki Asimaki Denis Graf Jacques Metzger

Arrhythmogenic cardiomyopathy (ACM), formerly known as arrhythmogenic right ventricular dysplasia, is a primary myocardial disorder characterized by ventricular arrhythmias and sudden cardiac death (SCD).1 Myocardial desmosomes are cell–cell junctions that reside within the intercalated disc. They consist of members of the cadherin family (desmocollin-2, desmoglein-2), which span the membrane mechanically coupling adjacent cells, and members of the plakin and armadillo families: plakoglobin (PKG), plakophilin-2 (PKP2), and desmoplakin (DSP1), which connect the cadherin complexes to the intermediate cytoskeleton filaments.

Desmoplakin

Plakoglobin

Desmosome

Intercalated disc

10.1016/j.hrcr.2018.06.013

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Citations (5)

Impact of Genetic Variant Reassessment on the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy Based on the 2010 Task Force Criteria

Circulation Genomic and Precision Medicine (2020)

Sarah Costa Argelia Medeiros‐Domingo Alessio Gasperetti Deniz Akdiş Wolfgang Berger

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy, which is associated with life-threatening ventricular arrhythmias. Approximately 60% of patients carry a putative disease-causing genetic variant, but interpretation of genetic test results can be challenging. The aims of this study were to systematically reclassify genetic variants in patients with ARVC and to assess the impact on ARVC diagnosis. Methods: This study included patients from the Multicenter Zurich ARVC Registry who hosted a genetic variant deemed to be associated with the disease. Reclassification of pathogenicity was performed according to the modified 2015 American College of Medical Genetics criteria. ARVC diagnosis (categories: definite, borderline, possible) based on the 2010 Task Force Criteria was reclassified after genetic readjudication. Results: In 79 patients bearing 80 unique genetic variants, n=47 (58.8%) genetic variants were reclassified, and reclassification was judged to be clinically relevant in n=33 (41.3%). Variants in plakophilin-2 ( PKP2 ) were shown to reclassify less frequently as compared with other genes ( PKP2 , n=1, 8.3%; desmosomal non- PKP2 , n=20, 66.7%; nondesmosomal, n=26, 68.4%; P =0.001for overall comparison; PKP2 versus desmosomal non- PKP2, P =0.001; PKP2 versus nondesmosomal, P <0.001). Genetic reclassification impacted ARVC diagnosis. Eight patients (10.1%) were downgraded from definite to borderline/possible disease at the time of initial genetic testing as well as last follow-up, respectively. Separate genetic reclassification in family members led to downgrading of n=5 (38.5%) variants. Conclusions: Given that approximately half of genetic variants were reclassified, with 10.1% of patients losing their definite disease status, accurate determination of variant pathogenicity is of utmost importance in the diagnosis of ARVC.

10.1161/circgen.120.003047

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Citations (17)

Failure rate and conductor externalization in the Biotronik Linox/Sorin Vigila implantable cardioverter-defibrillator lead

Heart Rhythm (2015)

Fabian Noti Anna Lam Nicole Klossner Jens Seiler Helge Servatius

Externalization

Lead (geology)

10.1016/j.hrthm.2015.12.038

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Citations (26)

Clinical Spectrum of SCN5A Channelopathy in Children with Primary Electrical Disease and Structurally Normal Hearts

Genes (2021)

Teresa Villarreal‐Molina Gabriela Paola García-Ordóñez Álvaro E. Reyes-Quintero Mayra Domínguez‐Pérez Leonor Jacobo‐Albavera

Sodium voltage-gated channel α subunit 5 (SCN5A)-mutations may cause an array of arrhythmogenic syndromes most frequently as an autosomal dominant trait, with incomplete penetrance, variable expressivity and male predominance. In the present study, we retrospectively describe a group of Mexican patients with SCN5A-disease causing variants in whom the onset of symptoms occurred in the pediatric age range. The study included 17 patients with clinical diagnosis of primary electrical disease, at least one SCN5A pathogenic or likely pathogenic mutation and age of onset <18 years, and all available first- and second-degree relatives. Fifteen patients (88.2%) were male, and sixteen independent variants were found (twelve missense, three truncating and one complex inframe deletion/insertion). The frequency of compound heterozygosity was remarkably high (3/17, 17.6%), with early childhood onset and severe disease. Overall, 70.6% of pediatric patients presented with overlap syndrome, 11.8% with isolated sick sinus syndrome, 11.8% with isolated Brugada syndrome (BrS) and 5.9% with isolated type 3 long QT syndrome (LQTS). A total of 24/45 SCN5A mutation carriers were affected (overall penetrance 53.3%), and penetrance was higher in males (63.3%, 19 affected/30 mutation carriers) than in females (33.3%, 5 affected/15 carriers). In conclusion, pediatric patients with SCNA-disease causing variants presented mainly as overlap syndrome, with predominant loss-of-function phenotypes of sick sinus syndrome (SSS), progressive cardiac conduction disease (PCCD) and ventricular arrhythmias.

Penetrance

Sick sinus syndrome

Compound heterozygosity

Expressivity

Channelopathy

10.3390/genes13010016

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Citations (11)