alpha 1-Syntrophin Variant Identified in Drug-Induced Long QT Syndrome Increases Late Sodium Current
DC Field | Value | Language |
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dc.contributor.author | Choi, Jong-Il | - |
dc.contributor.author | Wang, Chaojian | - |
dc.contributor.author | Thomas, Matthew J. | - |
dc.contributor.author | Pitt, Geoffrey S. | - |
dc.date.accessioned | 2021-09-04T01:19:52Z | - |
dc.date.available | 2021-09-04T01:19:52Z | - |
dc.date.created | 2021-06-17 | - |
dc.date.issued | 2016-03-30 | - |
dc.identifier.issn | 1932-6203 | - |
dc.identifier.uri | https://scholar.korea.ac.kr/handle/2021.sw.korea/89183 | - |
dc.description.abstract | Drug-induced long-QT syndrome (diLQTS) is often due to drug block of I-Kr, especially in genetically susceptible patients with subclinical mutations in the I-Kr-encoding KCHN2. Few variants in the cardiac Na(V)1.5 Na+ channel complex have been associated with diLQTS. We tested whether a novel SNTA1 (alpha 1-syntrophin) variant (p.E409Q) found in a patient with diLQTS increases late sodium current (INa-L), thereby providing a disease mechanism. Electrophysiological studies were performed in HEK293T cells co-expressing human Na(V)1.5/nNOS/PMCA4b with either wild type (WT) or SNTA1 variants (A390V-previously reported in congenital LQTS; and E409Q); and in adult rat ventricular cardiomyocytes infected with SNTA1 expressing adenoviruses (WT or one of the two SNTA1 variants). In HEK293T cells and in cardiomyocytes, there was no significant difference in the peak I-Na densities among the SNTA1 WT and variants. However, both variants increased INa-L (% of peak current) in HEK293T cells (0.58 +/- 0.10 in WT vs. 0.90 +/- 0.11 in A390V, p = 0.048; vs. 0.88 +/- 0.07 in E409Q, p = 0.023). In cardiomyocytes, INa-L was significantly increased by E409Q, but not by A390V compared to WT (0.49 +/- 0.14 in WT vs. 0.94 +/- 0.23 in A390V, p = 0.099; vs. 1.12 +/- 0.24 in E409Q, p = 0.019). We demonstrated that a novel SNTA1 variant is likely causative for diLQTS by augmenting INa-L. These data suggest that variants within the Na(V)1.5-interacting alpha 1-syntrophin are a potential mechanism for diLQTS, thereby expanding the concept that variants within congenital LQTS loci can cause diLQTS. | - |
dc.language | English | - |
dc.language.iso | en | - |
dc.publisher | PUBLIC LIBRARY SCIENCE | - |
dc.subject | FACTOR HOMOLOGOUS FACTORS | - |
dc.subject | SARCOLEMMAL CALCIUM-PUMP | - |
dc.subject | NITRIC-OXIDE SYNTHASE | - |
dc.subject | CARDIAC-ARRHYTHMIA | - |
dc.subject | HEART-FAILURE | - |
dc.subject | CHANNEL | - |
dc.subject | MUTATION | - |
dc.subject | COMPLEX | - |
dc.subject | REPOLARIZATION | - |
dc.subject | PROTEIN | - |
dc.title | alpha 1-Syntrophin Variant Identified in Drug-Induced Long QT Syndrome Increases Late Sodium Current | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Choi, Jong-Il | - |
dc.identifier.doi | 10.1371/journal.pone.0152355 | - |
dc.identifier.scopusid | 2-s2.0-84962647574 | - |
dc.identifier.wosid | 000373116500039 | - |
dc.identifier.bibliographicCitation | PLOS ONE, v.11, no.3 | - |
dc.relation.isPartOf | PLOS ONE | - |
dc.citation.title | PLOS ONE | - |
dc.citation.volume | 11 | - |
dc.citation.number | 3 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Science & Technology - Other Topics | - |
dc.relation.journalWebOfScienceCategory | Multidisciplinary Sciences | - |
dc.subject.keywordPlus | FACTOR HOMOLOGOUS FACTORS | - |
dc.subject.keywordPlus | SARCOLEMMAL CALCIUM-PUMP | - |
dc.subject.keywordPlus | NITRIC-OXIDE SYNTHASE | - |
dc.subject.keywordPlus | CARDIAC-ARRHYTHMIA | - |
dc.subject.keywordPlus | HEART-FAILURE | - |
dc.subject.keywordPlus | CHANNEL | - |
dc.subject.keywordPlus | MUTATION | - |
dc.subject.keywordPlus | COMPLEX | - |
dc.subject.keywordPlus | REPOLARIZATION | - |
dc.subject.keywordPlus | PROTEIN | - |
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