A novel CACNA1C mutation identified in a patient with Timothy syndrome without syndactyly exerts both marked loss- and gain-of-function effects Junichi.

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Date of download: 9/18/2016 Copyright © The American College of Cardiology. All rights reserved. From: A Novel SCN5A Gain-of-Function Mutation M1875T Associated.

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A novel CACNA1C mutation identified in a patient with Timothy syndrome without syndactyly exerts both marked loss- and gain-of-function effects Junichi Ozawa, MD, PhD, Seiko Ohno, MD, PhD, Hideki Saito, MD, Akihiko Saitoh, MD, PhD, Hiroshi Matsuura, MD, PhD, Minoru Horie, MD, PhD HeartRhythm Case Reports Volume 4, Issue 7, Pages 273-277 (July 2018) DOI: 10.1016/j.hrcr.2018.03.003 Copyright © 2018 Heart Rhythm Society Terms and Conditions

Figure 1 Electrocardiograms. A: One year after the cardiac event. B: Day of admission. C: At left: Electropherograms of p.S643F. At right: Amino acid sequence alignments of p.S643F. D: Predicted topology of the CaV1.2 α subunit. Pink-filled circles indicate positions of mutations causing TS, and orange-filled triangles those of mutations causing TS without syndactyly. Yellow-filled diamonds denote mutations causing only LQTS phenotype without extracardiac features. AID = α1 interacting domain; D = domain; LQTS = long QT syndrome; S = segment; TS = Timothy syndrome. HeartRhythm Case Reports 2018 4, 273-277DOI: (10.1016/j.hrcr.2018.03.003) Copyright © 2018 Heart Rhythm Society Terms and Conditions

Figure 2 Functional analysis of the mutant Cav1.2 channels. A: Whole-cell current representative recordings of wild-type (WT) and mutant Ca2+ channels. Peak inward current-voltage relationships were constructed by applying 1-s pulses from a holding potential of −70 mV to potentials ranging from −50 to +40 mV (upper). Representative traces of currents elicited at 0 mV and +20 mV from a holding potential of −70 mV at baseline (lower). B: Peak inward current-voltage relationship for WT (black circles, n = 18) and S643F (red triangles, n = 15). Peak inward currents were normalized to cell capacitance to give a measure of Ca2+ current density. ∗P < .05, ∗∗P < .01. C: The relationship between remaining currents at 500 ms depolarization and voltage for WT (black circles, n = 18) and S643F (red triangles, n = 15). D: Conductance-voltage activation curves for WT (black circles, n = 18) and S643F (red triangles, n = 15). E: Time constants for the voltage dependence of inactivation in WT (black circles, n = 18) and S643F (red triangles, n = 15). ∗P < .05, ∗∗P < .01. HeartRhythm Case Reports 2018 4, 273-277DOI: (10.1016/j.hrcr.2018.03.003) Copyright © 2018 Heart Rhythm Society Terms and Conditions

Figure 3 A: To study the voltage dependence of inactivation, two-step voltage protocol, as indicated in the bottom right inset, was employed. Upper two sets traces are representative records. B: Conductance-voltage inactivation curves of Ca2+ current for wild-type (WT) (black circles, n = 15) and S643F (red triangles, n = 11). C: Conductance-voltage inactivation curves of Ba2+ current for WT (black circles, n = 10) and S643F (red triangles, n = 7). HeartRhythm Case Reports 2018 4, 273-277DOI: (10.1016/j.hrcr.2018.03.003) Copyright © 2018 Heart Rhythm Society Terms and Conditions

Supplementary Figure 1 ECGs demonstrate T wave inversion in all leads except aVR (A) and torsades de pointes (B). HeartRhythm Case Reports 2018 4, 273-277DOI: (10.1016/j.hrcr.2018.03.003) Copyright © 2018 Heart Rhythm Society Terms and Conditions