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Functional phenotype variations of two novel K V 7.1 mutations identified in patients with Long QT syndrome
Author(s) -
Hammami Bomholtz Sofia,
Refaat Marwan,
Buur Steffensen Annette,
David JensPeter,
Espinosa Karin,
Nussbaum Robert,
Wojciak Julianne,
Hjorth Bentzen Bo,
Scheinman Melvin,
Schmitt Nicole
Publication year - 2020
Publication title -
pacing and clinical electrophysiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.686
H-Index - 101
eISSN - 1540-8159
pISSN - 0147-8389
DOI - 10.1111/pace.13870
Subject(s) - long qt syndrome , medicine , repolarization , phenotype , membrane potential , patch clamp , mutation , mutant , potassium channel , sudden death , sudden cardiac death , endoplasmic reticulum , electrophysiology , wild type , afterdepolarization , cardiology , endocrinology , qt interval , microbiology and biotechnology , biophysics , genetics , biology , gene
Background The slow delayed rectifier potassium current I Ks is crucial for the repolarization of the cardiac action potential. It is conducted by the voltage‐gated channel K V 7.1 encoded by KCNQ1 , together with its β‐subunit KCNE1. Loss‐of‐function (LOF) mutations in KCNQ1 have been associated with heritable cardiac arrhythmias such as Long QT syndrome (LQTS). This disease is characterized by prolonged ventricular repolarization and propensity to ventricular tachyarrhythmia that may lead to syncope, cardiac arrest, and sudden death. We aimed to functionally characterize two K V 7.1 mutations (p.A150T and p.L374H) identified in two independent LQTS patients with different severity of disease phenotype, family history, and co‐segregation of LQTS. Methods We performed whole‐cell patch clamp recordings in CHO‐K1 cells, and confocal imaging in Madin‐Darby Canine Kidney (MDCK) cells. Results I Ks ‐A150T showed significantly decreased current amplitudes from above +20 mV (approximately 52% decrease at +40 mV), but demonstrated cell membrane localization similar to wild‐type (WT). I Ks ‐L374H, however, exhibited a complete LOF compared to WT channels. Confocal imaging showed endoplasmic reticulum retention of the channel in MDCK cells. Mimicking the heterozygous state of the patients by co‐expressing WT and mutant subunits resulted in an approximately 22% decrease in current at +40 mV for A150T. The L374H mutation showed a more pronounced effect (62% reduction at +40 mV compared to WT channel). Conclusion Both mutations, K V 7.1 A150T and L374H, led to loss of channel function. The degree of LOF may mirror the disease phenotype observed in the patients.