http://purl.uniprot.org/citations/21349352 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
http://purl.uniprot.org/citations/21349352 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
http://purl.uniprot.org/citations/21349352 | http://www.w3.org/2000/01/rdf-schema#comment | "BackgroundBrugada 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.MethodsComprehensive 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.ResultsTwo 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.ConclusionsThese 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."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.org/dc/terms/identifier | "doi:10.1016/j.hrthm.2011.02.021"xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.org/dc/terms/identifier | "doi:10.1016/j.hrthm.2011.02.021"xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Ye D."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Ye D."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Ackerman M.J."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Ackerman M.J."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Tester D.J."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Tester D.J."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Antzelevitch C."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Antzelevitch C."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Giudicessi J.R."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Giudicessi J.R."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Nesterenko V.V."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Nesterenko V.V."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Schwartz P.J."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Schwartz P.J."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Crotti L."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Crotti L."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Albertson R.M."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Albertson R.M."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Mugione A."xsd:string |
http://purl.uniprot.org/citations/21349352 | http://purl.uniprot.org/core/author | "Mugione A."xsd:string |