Abstract

KCNQ1 encodes the voltage-gated potassium (Kv) channel KCNQ1, also known as KvLQT1 or Kv7.1. Together with its ß-subunit KCNE1, also denoted as minK, this channel generates the slowly activating cardiac delayed rectifier current IKs, which is a key regulator of the heart rate dependent adaptation of the cardiac action potential duration (APD). Loss-of-function mutations in KCNQ1 cause congenital long QT1 (LQT1) syndrome, characterized by a delayed cardiac repolarization and a prolonged QT interval in the surface electrocardiogram. Autosomal dominant loss-of-function mutations in KCNQ1 result in long QT syndrome, called Romano–Ward Syndrome (RWS), while autosomal recessive mutations lead to Jervell and Lange-Nielsen syndrome (JLNS), associated with deafness. Here, we identified a homozygous KCNQ1 mutation, c.1892_1893insC (p.P631fs*20), in a patient with an isolated LQT syndrome (LQTS) without hearing loss. Nevertheless, the inheritance trait is autosomal recessive, with heterozygous family members being asymptomatic. The results of the electrophysiological characterization of the mutant, using voltage-clamp recordings in Xenopus laevis oocytes, are in agreement with an autosomal recessive disorder, since the IKs reduction was only observed in homomeric mutants, but not in heteromeric IKs channel complexes containing wild-type channel subunits. We found that KCNE1 rescues the KCNQ1 loss-of-function in mutant IKs channel complexes when they contain wild-type KCNQ1 subunits, as found in the heterozygous state. Action potential modellings confirmed that the recessive c.1892_1893insC LQT1 mutation only affects the APD of homozygous mutation carriers. Thus, our study provides the molecular mechanism for an atypical autosomal recessive LQT trait that lacks hearing impairment.

Highlights

  • There are two important potassium currents responsible for the late phase of repolarization of the cardiac action potential (AP): the rapid delayed rectifier potassium current (IKr ) and the slow rectifier potassium current (IKs ) [1,2]

  • The index patient (IP) did not suffer from hearing loss and she was diagnosed with multiple sclerosis

  • Since in cardiac tissue KCNQ1 is expressed in a complex with its ß-subunit KCNE1 to form the IKs, we examined the electrophysiology of the KCNQ1P631fs*20 mutant

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Summary

Introduction

There are two important potassium currents responsible for the late phase of repolarization of the cardiac action potential (AP): the rapid delayed rectifier potassium current (IKr ) and the slow rectifier potassium current (IKs ) [1,2]. The IKs current is generated by KCNQ1 channels, which coassemble with their cardiac ß-subunit KCNE1, known as minK [4]. KCNE1 is the primary accessory subunit of KCNQ1 [9], causing drastic changes to the electrophysiological characteristics of the KCNQ1 channel: current amplitudes are increased, activation is delayed and voltagedependence of activation is shifted to more positive potentials [4,5]. KCNE1 is essential for the targeting of KCNQ1 to the surface membrane and its respective stability in the plasma membrane This becomes evident as in MinK (KCNE1) knock-out mice, no KCNQ1 immunostaining of the luminal membrane of dark cells of the vestibular system was observed [10]. KCNE1 mutations were identified to be clinically relevant in the human heart and inner ear [10]

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