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• W2155488508 abstract "An LQTS6 M54T Mutation and Sinus Node Dysfunction Background Sinus node (SN) dysfunction is observed in some long‐QT syndrome (LQTS) patients, but has not been studied as a function of LQTS genotype. LQTS6 involves mutations in the hERG β‐subunit MiRP1, which also interacts with hyperpolarization‐activated, cyclic nucleotide gated (HCN) channels—the molecular correlate of SN pacemaker current (I f ). An LQTS registry search identified a 55‐year male with M54T MiRP1 mutation, history of sinus bradycardia (39–56 bpm), and prolonged QTc. Objective We tested if LQTS6 incorporates sinus bradycardia due to abnormal I f . Methods We transiently co‐transfected neonatal rat ventricular myocytes (to study currents in a myocyte background) with human HCN4 (hHCN4, primary SN isoform) or human HCN2 (hHCN2) and one of the following: empty vector, wild‐type hMiRP1 (WT), M54T hMiRP1 (M54T). Current amplitude, voltage dependence, and kinetics were measured by whole cell patch clamp. Results M54T co‐expression decreased HCN4 current density by 80% compared to hHCN4 alone or with WT, and also slowed HCN4 activation at physiologically relevant voltages. Neither WT nor M54T altered HCN4 voltage dependence. A computer simulation predicts that these changes in HCN4 current would decrease rate and be additive with published effects of M54T mutation on hERG kinetics on rate. Conclusions We conclude that M54T LQTS6 mutation can cause sinus bradycardia through effects on both hERG and HCN currents. Patients with other LQTS6 mutations should be examined for SN dysfunction, and the effect on HCN current determined." @default.
• W2155488508 created "2016-06-24" @default.
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• W2155488508 date "2013-04-30" @default.
• W2155488508 modified "2023-10-13" @default.
• W2155488508 title "An LQTS6 MiRP1 Mutation Suppresses Pacemaker Current and is Associated with Sinus Bradycardia" @default.
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• W2155488508 doi "https://doi.org/10.1111/jce.12163" @default.
• W2155488508 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4059362" @default.
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