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Article: Nedd4L as a modifier for resuming trafficking defects of KCNQ1-Y111C in Romano Ward Syndrome (LQT1)

TitleNedd4L as a modifier for resuming trafficking defects of KCNQ1-Y111C in Romano Ward Syndrome (LQT1)
Authors
Issue Date2015
Citation
Journal of Clinical Investigation (Forthcoming) How to Cite?
AbstractA highly conserved Y111C mutation at N-terminal of KCNQ1 has been implicated in Romano Ward (LQT1) syndrome due to trafficking defeats. In current study, a pair of KCNQ1-Y111C mutation familial carriers presented with symptomatic (S; QTc = 490 ms) and asymptomatic (AS; QTc = 417 ms) phenotypes. We hypothesize trafficking resume would be the possible protective modifying mechanism, which would be studied by LQTS-patient specific human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMCs). Membrane surface expression of transgenic KCNE1-Q1 VSV tag indicated KCNE1-Q1-Y111C in AS-hiPSC-CMC. On the contrary, in WT- and S-hiPSC-CMC KCNE1-Q1 Y111C was retained in ER. Multielectrode array (MEA) recording revealed a significantly prolonged field potential duration (FPD) (*p<0.05) which was in agreement with significant prolongation of action potential duration (APD) observed in S-hiPSC-CMC as analyzed by whole cell patch clamping. The confirmed phenotype in hiPSC-CMC platform could be explained by the significant loss of IKs in S-iPSC-CMC either bearing with transgenic KCNE1-Q1. Further protein interaction studies showed that KCNQ1-Y111C is more rapidly degraded in presence of Nedd4-2. The ubiquitination-related Nedd4-2 interacting with KCNQ1-Y111C was activated by dephosphorylation. siRNA knockdown of Nedd4-2 in WT and S-hiPSC-CMC resume levels and trafficking of the ion channels.
Persistent Identifierhttp://hdl.handle.net/10722/214376
ISSN
2015 Impact Factor: 12.575
2015 SCImago Journal Rankings: 8.764

 

DC FieldValueLanguage
dc.contributor.authorLee, YK-
dc.contributor.authorSala, L-
dc.contributor.authorMura, M-
dc.contributor.authorRocchetti, M-
dc.contributor.authorCrotti, L-
dc.contributor.authorSchwartz, PJ-
dc.contributor.authorZaza, A-
dc.contributor.authorTse, HF-
dc.contributor.authorGnecchi, M-
dc.date.accessioned2015-08-21T11:21:02Z-
dc.date.available2015-08-21T11:21:02Z-
dc.date.issued2015-
dc.identifier.citationJournal of Clinical Investigation (Forthcoming)-
dc.identifier.issn0021-9738-
dc.identifier.urihttp://hdl.handle.net/10722/214376-
dc.description.abstractA highly conserved Y111C mutation at N-terminal of KCNQ1 has been implicated in Romano Ward (LQT1) syndrome due to trafficking defeats. In current study, a pair of KCNQ1-Y111C mutation familial carriers presented with symptomatic (S; QTc = 490 ms) and asymptomatic (AS; QTc = 417 ms) phenotypes. We hypothesize trafficking resume would be the possible protective modifying mechanism, which would be studied by LQTS-patient specific human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMCs). Membrane surface expression of transgenic KCNE1-Q1 VSV tag indicated KCNE1-Q1-Y111C in AS-hiPSC-CMC. On the contrary, in WT- and S-hiPSC-CMC KCNE1-Q1 Y111C was retained in ER. Multielectrode array (MEA) recording revealed a significantly prolonged field potential duration (FPD) (*p<0.05) which was in agreement with significant prolongation of action potential duration (APD) observed in S-hiPSC-CMC as analyzed by whole cell patch clamping. The confirmed phenotype in hiPSC-CMC platform could be explained by the significant loss of IKs in S-iPSC-CMC either bearing with transgenic KCNE1-Q1. Further protein interaction studies showed that KCNQ1-Y111C is more rapidly degraded in presence of Nedd4-2. The ubiquitination-related Nedd4-2 interacting with KCNQ1-Y111C was activated by dephosphorylation. siRNA knockdown of Nedd4-2 in WT and S-hiPSC-CMC resume levels and trafficking of the ion channels.-
dc.languageeng-
dc.relation.ispartofJournal of Clinical Investigation-
dc.titleNedd4L as a modifier for resuming trafficking defects of KCNQ1-Y111C in Romano Ward Syndrome (LQT1)-
dc.typeArticle-
dc.identifier.emailLee, YK: carol801@hku.hk-
dc.identifier.emailTse, HF: hftse@hkucc.hku.hk-
dc.identifier.authorityTse, HF=rp00428-
dc.identifier.hkuros248948-

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