The Mutation P.T613a in the Pore Helix of the Kv 11.1 Potassium Channel is Associated with Long Qt Syndrome
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The Mutation P.T613a in the Pore Helix of the Kv 11.1 Potassium Channel is Associated with Long Qt Syndrome. / Poulsen, Kristian L; Hotait, Mostafa; Calloe, Kirstine; Klaerke, Dan A; Rebeiz, Abdallah; Nemer, Georges; Tejada, Maria A; Refaat, Marwan M.
In: Pacing and Clinical Electrophysiology, Vol. 38, No. 11, 11.2015, p. 1304–1309.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - The Mutation P.T613a in the Pore Helix of the Kv 11.1 Potassium Channel is Associated with Long Qt Syndrome
AU - Poulsen, Kristian L
AU - Hotait, Mostafa
AU - Calloe, Kirstine
AU - Klaerke, Dan A
AU - Rebeiz, Abdallah
AU - Nemer, Georges
AU - Tejada, Maria A
AU - Refaat, Marwan M
N1 - © 2015 Wiley Periodicals, Inc.
PY - 2015/11
Y1 - 2015/11
N2 - BACKGROUND: Loss-of-function mutations in the voltage gated potassium channel Kv 11.1 have been associated with the Long QT Syndrome (LQTS) type 2. We identified the p.T613A mutation in Kv 11.1 in a family with LQTS. T613A is located in the outer part of the pore helix, a structure that is involved in C-type inactivation. Here we characterize the effect of p.T613A on the functional properties of KV 11.1.METHODS: The p.T613A mutation was introduced into KV 11.1 (T613A). Wild-type KV 11.1 (WT) and T613A were expressed in Xenopus laevis oocytes and characterized by two-electrode-voltage-clamp.RESULTS: T613A currents were reduced to <20% of WT currents and T613A induced a minor negative shift in half maximal rectification, indicating that the voltage-dependent onset on inactivation occurred at more negative voltages compared to WT. Co-expression of T613A with WT revealed intermediate phenotype and there was no dominant negative effect of T613A.CONCLUSION: These findings suggest that p.T613A causes a loss-of-function of Kv 11.1. This results in a reduced repolarizing reserve which may result in LQTS2 and sudden cardiac death.
AB - BACKGROUND: Loss-of-function mutations in the voltage gated potassium channel Kv 11.1 have been associated with the Long QT Syndrome (LQTS) type 2. We identified the p.T613A mutation in Kv 11.1 in a family with LQTS. T613A is located in the outer part of the pore helix, a structure that is involved in C-type inactivation. Here we characterize the effect of p.T613A on the functional properties of KV 11.1.METHODS: The p.T613A mutation was introduced into KV 11.1 (T613A). Wild-type KV 11.1 (WT) and T613A were expressed in Xenopus laevis oocytes and characterized by two-electrode-voltage-clamp.RESULTS: T613A currents were reduced to <20% of WT currents and T613A induced a minor negative shift in half maximal rectification, indicating that the voltage-dependent onset on inactivation occurred at more negative voltages compared to WT. Co-expression of T613A with WT revealed intermediate phenotype and there was no dominant negative effect of T613A.CONCLUSION: These findings suggest that p.T613A causes a loss-of-function of Kv 11.1. This results in a reduced repolarizing reserve which may result in LQTS2 and sudden cardiac death.
U2 - 10.1111/pace.12693
DO - 10.1111/pace.12693
M3 - Journal article
C2 - 26173150
VL - 38
SP - 1304
EP - 1309
JO - PACE - Pacing and Clinical Electrophysiology
JF - PACE - Pacing and Clinical Electrophysiology
SN - 0147-8389
IS - 11
ER -
ID: 144206431