| Autor: |
Ana Isabel Moreno-Manuel, Lilian K Gutiérrez, María Linarejos Vera-Pedrosa, Francisco Miguel Cruz, Francisco José Bermúdez-Jiménez, Isabel Martínez-Carrascoso, Patricia Sánchez-Pérez, Álvaro Macías, José Jalife |
| Přispěvatelé: |
Instituto de Salud Carlos III, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Fundación La Caixa, Fundación La Marató TV3, Unión Europea. Comisión Europea. H2020, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia y Universidades (España), Ministerio de Economía y Competitividad (España), Comunidad de Madrid (España), Fundación ProCNIC, Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España), Ministerio de Universidades (España) |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Cardiovascular Research |
| Popis: |
Andersen Tawil Syndrome (ATS) is a rare inheritable disease associated with loss-of-function mutations in KCNJ2, the gene coding the strong inward rectifier potassium channel Kir2.1, which forms an essential membrane protein controlling cardiac excitability. ATS is usually marked by a triad of periodic paralysis, life-threatening cardiac arrhythmias and dysmorphic features, but its expression is variable and not all patients with a phenotype linked to ATS have a known genetic alteration. The mechanisms underlying this arrhythmogenic syndrome are poorly understood. Knowing such mechanisms would be essential to distinguish ATS from other channelopathies with overlapping phenotypes and to develop individualized therapies. For example, the recently suggested role of Kir2.1 as a countercurrent to sarcoplasmic calcium reuptake might explain the arrhythmogenic mechanisms of ATS and its overlap with catecholaminergic polymorphic ventricular tachycardia (CPVT). Here we summarize current knowledge on the mechanisms of arrhythmias leading to sudden cardiac death in ATS. We first provide an overview of the syndrome and its pathophysiology, from the patient´s bedside to the protein, and discuss the role of essential regulators and interactors that could play a role in cases of ATS. The review highlights novel ideas related to some post-translational channel interactions with partner proteins that might help define the molecular bases of the arrhythmia phenotype. We then propose a new all-embracing classification of the currently known ATS loss-of-function mutations according to their position in the Kir2.1 channel structure and their functional implications. We also discuss specific ATS pathogenic variants, their clinical manifestations and treatment stratification. The goal is to provide a deeper mechanistic understanding of the syndrome toward the development of novel targets and personalized treatment strategies. This work has been supported by SQTS Project (PI20/01220) of the public call Proyectos de investigación en salud 2020 (PI-FIS-2020) funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union, (FEDER/FSE), ‘Una manera de hacer Europa’/’El FSE invierte en tu futuro’; Fundación ‘La Caixa’: Macromoleculopathies (LCF/PR/ HR19/52160013) of the call HEALTH RESEARCH 2018; Genotype Specific Arrhythmogenic Mechanisms in Andersen-Tawil Syndrome (736/C/2020) of the call Ayudas a la investigación en enfermedades raras 2020 (LAMARATO-2020)’ amb el suport de la Fundació La Marató de TV3; the European Union’s Horizon 2020 research and innovation programme under grant agreement (GA-965286) (‘Funded by the European Union. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them.’); the Dynamic Microscopy and Imaging Unit - ICTS-ReDib Grant ICTS-2018-04-CNIC-16 funded by MCIN/AEI/10.13039/501100011033 and ERDF ‘A way of making Europe’; EQC2018-005070-P funded by MCIN/AEI/10.13039/ 501100011033 and FEDER ‘Una manera de hacer Europa’; AIM-M holds a FPU contract (FPU20/01569) from Ministerio de Universidades; LKG holds a FPI contract (PRE2018-083530), Ministerio de Economía y Competitividad de España co-funded by Fondo Social Europeo ‘El Fondo Social Europeo invierte en tu futuro’, attached to the Project SEV-2015-0505-18-2; MLVP holded a contract (PEJD-2019-PRE/ BMD-15982) funded by Consejería de Educación e Investigación de la Comunidad de Madrid y Fondo Social Europeo ‘El FSE invierte en tu futuro’; IM-C holds a PFIS contract (FI21/00243) funded by Instituto de Salud Carlos III and Fondo Social Europeo Plus (FSE+), ‘Cofunded by the European Union’; The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation and is a Severo Ochoa Centre of Excellence (grant CEX2020-001041-S funded by MICIN/AEI/ 10.13039/501100011033). Sí |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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