Abstract
BackgroundAtrial fibrillation (AF) is the most common arrhythmia. The potassium current IKs is essential for cardiac repolarization. Gain-of-function mutations in KV7.1, the pore-forming α-subunit of the IKs channel, have been associated with AF. We hypothesized that early-onset lone AF is associated with mutations in the IKs channel regulatory subunit KCNE1.MethodsIn 209 unrelated early-onset lone AF patients (< 40 years) the entire coding sequence of KCNE1 was bidirectionally sequenced. We analyzed the identified KCNE1 mutants electrophysiologically in heterologous expression systems.ResultsTwo non-synonymous mutations G25V and G60D were found in KCNE1 that were not present in the control group (n = 432 alleles) and that have not previously been reported in any publicly available databases or in the exom variant server holding exom data from more than 10.000 alleles. Proband 1 (female, age 45, G25V) had onset of paroxysmal AF at the age of 39 years. Proband 2 (G60D) was diagnosed with lone AF at the age of 33 years. The patient has inherited the mutation from his mother, who also has AF. Both probands had no mutations in genes previously associated with AF. In heterologous expression systems, both mutants showed significant gain-of-function for IKs both with respect to steady-state current levels, kinetic parameters, and heart rate-dependent modulation.ConclusionsMutations in KV7.1 leading to gain-of-function of IKs current have previously been described in lone AF, yet this is the first time a mutation in the beta-subunit KCNE1 is associated with the disease. This finding further supports the hypothesis that increased potassium current enhances AF susceptibility.
Highlights
Atrial fibrillation (AF) is the most common arrhythmia
The positions G25 and G60 in KCNE1 are highly conserved across species suggesting a functional importance (Additional file 1: Figure S1)
When summarizing the current measurements from oocytes expressing either KCNE1-WT, KCNE-G25V or KCNE-G60D together with KV7.1, subjected to 5 s depolarizing potentials from a holding potential of -80 mV we found that both mutations caused an increase in steady-state current amplitude at all activating potentials (Figure 2C, Additional file 1: Figure S2)
Summary
Atrial fibrillation (AF) is the most common arrhythmia. The potassium current IKs is essential for cardiac repolarization. We hypothesized that early-onset lone AF is associated with mutations in the IKs channel regulatory subunit KCNE1. Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia It is responsible for considerable morbidity and mortality, and its population prevalence has reached epidemic proportions, affecting almost seven million patients in the European Union and the USA combined [1,2,3,4]. 10-20% of patients suffering from AF are younger than 60 years of age and lack the traditional risk factors for AF. These patients are considered as having “lone” AF [2]. Early-onset lone AF has been suggested to be a primary electrical disease caused by disturbances in ionic currents. A genetic cause of these types of electrical disturbances is becoming increasingly recognized [6]
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