A SPRY1 domain cardiac ryanodine receptor variant associated with short-coupled torsade de pointes.
Sci Rep
; 11(1): 5243, 2021 03 04.
Article
em En
| MEDLINE
| ID: mdl-33664309
ABSTRACT
Idiopathic ventricular fibrillation (IVF) causes sudden death in young adult patients without structural or ischemic heart disease. Most IVF cases are sporadic and some patients present with short-coupled torsade de pointes, the genetics of which are poorly understood. A man who had a first syncope at the age of 35 presented with frequent short-coupled premature ventricular beats with bursts of polymorphic ventricular tachycardia and then died suddenly. By exome sequencing, we identified three rare variants p.I784F in the SPRY1 of the ryanodine receptor 2 (RyR2), p.A96S in connexin 40 (Cx40), reported to affect electrical coupling and cardiac conduction, and a nonsense p.R244X in the cardiac-specific troponin I-interacting kinase (TNNI3K). We assessed intracellular Ca2+ handling in WT and mutant human RYR2 transfected HEK293 cells by fluorescent microscopy and an enhanced store overload-induced Ca2+ release in response to cytosolic Ca2+ was observed in RyR2-I784F cells. In addition, crystal structures and thermal melting temperatures revealed a conformational change in the I784F-SPRY1 domain compared to the WT-domain. The novel RyR2-I784F variant in SPRY1 domain causes a leaky channel under non-stress conditions. The presence of several variants affecting Ca2+ handling and cardiac conduction suggests a possible oligogenic origin for the ectopies originating from Purkinje fibres.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
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Fibrilação Ventricular
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Proteínas Serina-Treonina Quinases
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Isquemia Miocárdica
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Canal de Liberação de Cálcio do Receptor de Rianodina
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Proteínas de Membrana
Tipo de estudo:
Risk_factors_studies
Limite:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Sci Rep
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
França