Key result
Loss-of-function TRPM4 variants occur in 2.2% of LQTS patients lacking major gene mutations.
Why the study?
Not all LQTS patients have identified mutations in major LQTS genes, suggesting the existence of unknown causal genes such as TRPM4.
Are TRPM4 variants present in LQTS patients without mutations in major LQTS genes, and do they alter channel function?
Cohort (n=178)
Yes
Are TRPM4 variants present in LQTS patients without mutations in major LQTS genes, and do they alter channel function?
TRPM4 variants may be a rare cause of long QT syndrome, expanding the genetic basis of the disease beyond classical ion channel mutations.
May implicate TRPM4 in select mutation-negative LQTS; extends genetic spectrum but leaves open clinical testing utility.
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: 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.
No takes yet. Share an insight, caveat, or question.
Hof et al. (2017) conducted a cohort in Long QT syndrome (n=178). TRPM4 variants vs. Control populations / Wild-type TRPM4 was evaluated on Prevalence of TRPM4 variants. TRPM4 variants were identified in 2.2% of patients with long QT syndrome lacking mutations in major LQTS genes, and these variants demonstrated a significant loss of channel function in vitro.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: