Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome.
Heart Rhythm
; 8(7): 1024-32, 2011 Jul.
Article
em En
| MEDLINE
| ID: mdl-21349352
ABSTRACT
BACKGROUND:
Brugada syndrome (BrS) is a sudden death-predisposing genetic condition characterized electrocardiographically by ST segment elevation in the leads V(1)-V(3). Given the prominent role of the transient outward current (I(to)) in BrS pathogenesis, we hypothesized that rare gain-of-function mutations in KCND3 may serve as a pathogenic substrate for BrS.METHODS:
Comprehensive mutational analysis of KCND3-encoded Kv4.3 (I(to)) was conducted using polymerase chain reaction, denaturing high performance liquid chromatography, and direct sequencing of DNA derived from 86 unrelated BrS1-8 genotype-negative BrS patients. DNA from 780 healthy individuals was examined to assess allelic frequency for nonsynonymous variants. Putative BrS-associated Kv4.3 mutations were engineered and coexpressed with wild-type KChIP2 in HEK293 cells. Wild-type and mutant I(to) ion currents were recorded using whole-cell patch clamp.RESULTS:
Two BrS1-8 genotype-negative cases possessed novel Kv4.3 missense mutations. Both Kv4.3-L450F and Kv4.3-G600R were absent in 1,560 reference alleles and involved residues highly conserved across species. Both Kv4.3-L450F and Kv4.3-G600R demonstrated a gain-of-function phenotype, increasing peak I(to) current density by 146.2% (n = 15, P <.05) and 50.4% (n = 15, P <.05), respectively. Simulations using a Luo-Rudy II action potential (AP) model demonstrated the stable loss of the AP dome as a result of the increased I(to) maximal conductance associated with the heterozygous expression of either L450F or G600R.CONCLUSIONS:
These findings provide the first molecular and functional evidence implicating novel KCND3 gain-of-function mutations in the pathogenesis and phenotypic expression of BrS, with the potential for a lethal arrhythmia being precipitated by a genetically enhanced I(to) current gradient within the right ventricle where KCND3 expression is the highest.
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Base de dados:
MEDLINE
Assunto principal:
DNA
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Mutação de Sentido Incorreto
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Canais de Potássio Shal
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Síndrome de Brugada
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Miocárdio
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article