TRPM4 non-selective cation channel variants in long QT syndrome

Abstract

Background: Long QT syndrome (LQTS) is an inherited arrhythmic disorder characterized by prolongation of the QT interval, a risk of syncope, and sudden death. There are already a number of causal genes in LQTS, but not all LQTS patients have an identified mutation, which suggests LQTS unknown genes.

Methods: A cohort of 178 LQTS patients, with no mutations in the 3 major LQTS genes (KCNQ1, KCNH2, and SCN5A), was screened for mutations in the transient potential melastatin 4 gene (TRPM4).

Results: Four TRPM4 variants (2.2% of the cohort) were found to change highly conserved amino-acids and were either very rare or absent from control populations. Therefore, these four TRPM4 variants were predicted to be disease causing. Furthermore, no mutations were found in the DNA of these TRPM4 variant carriers in any of the 13 major long QT syndrome genes. Two of these variants were further studied by electrophysiology (p.Val441Met and p.Arg499Pro). Both variants showed a classical TRPM4 outward rectifying current, but the current was reduced by 61 and 90% respectively, compared to wild type TRPM4 current.

Conclusions: This study supports the view that TRPM4 could account for a small percentage of LQTS patients. TRPM4 contribution to the QT interval might be multifactorial by modulating whole cell current but also, as shown in Trpm4^-/- mice, by modulating cardiomyocyte proliferation. TRPM4 enlarges the subgroup of LQT genes (KCNJ2 in Andersen syndrome and CACNA1C in Timothy syndrome) known to increase the QT interval through a more complex pleiotropic effect than merely action potential alteration.

Keywords: Arrhythmia; Electrophysiology; Gene mutation; Long QT syndrome; Outward rectifying current; TRPM4.

Fig. 1

ECG of Patient 1: This patient was 70 years old at the time of ECG. He had a left anterior hemiblock and a QTc interval at 539 ms (QT 560 ms and heart rate 56/min)

Fig. 2

ECG of Patient 2: The boy was 9 years old at the time recording of this ECG. He had a heart rate at 86/min, QT 394 ms and QTc 471 ms as measured automatically

Fig. 3

ECG of Patient 3: This 69-year-old female patient had a heart rhythm at 68/min, QT 440 ms and QTc 469 ms

Fig. 4

Holter ECG of Patient 3: This recording showed a short bout of ventricular arrhythmia occurring the afternoon of her morning syncope

Fig. 5

ECG of Patient 4: This boy had a heart rate at 58/min, QT 498 ms and QTc 490 ms

Fig. 6

Biophysical properties of currents from HEK-293 cells transfected with WT and TRPM4 variants. a Representative current tracings recorded in the whole-cell configuration (ramp protocol under the traces) (b) Mean current densities for WT and variants estimated using the maximal current recorded during the ending step of 20 ms at Vm = +100 mV (see a). c Rectification factor estimated by the current amplitude at +100 mV divided by the current amplitude at −60 mV . *p < 0.05, Error bar: standard error of the mean. Number of experiments is indicated in bars. Abbreviations: NT: Non-Transfected; WT: Wild-type