Increased L-type calcium current causes action potential prolongation in Jervell and Lange-Nielsen syndrome and is a...

KCNQ1 loss of function variants are thought to cause type 1 long QT syndrome by reducing I _Ks. However, we have recently reported that pharmacologic block of I _Ks in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) produced minimal increases in action potential duration at 90% repolarization (APD₉₀), while genetic loss of KCNQ1 markedly prolonged APD₉₀. We sought here to define mechanisms underlying APD prolongation by genetic loss of KCNQ1.

We studied iPSC-CMs from population controls, an isogenic KCNQ1 knock out (KO) line created by a homozygous edit for the R518X loss of function variant, and 2 unrelated patients with the Jervell and Lange-Nielsen syndrome (JLN) due to compound heterozygosity for loss of function KCNQ1 variants.

In both JLN and the KCNQ1-KO lines, I _Ks was absent, APD₉₀ was markedly prolonged, and L-type Ca channel (LTCC) current (I _Ca-L) was significantly increased, 2-3-fold, compared to the control cells with no change in kinetics or gating. RNA-sequencing identified 298 and 584 genes that were up- and down-regulated, respectively, by KCNQ1-KO compared to the isogenic control cells. Gene ontology analysis identified down-regulation of 6 Ca²⁺ channel negative regulatory genes (p=0.0002, FDR=0.02), and in knockdown experiments in wild-type iPSC-CMs, three of these, CBARP, FKBP1B, and RRAD, increased I _Ca-L, and RRAD increased APD₉₀. A therapeutic low concentration (1 μM) of the Ca channel antagonist diltiazem significantly shortened APD₉₀ in the two JLN cell lines and in KCNQ1-KO cells. A single low dose of intravenous diltiazem in one of the JLN patients shortened QTc.

These data further support the concept that delayed repolarization in JLN cannot be explained solely by loss of I _Ks. Our findings demonstrate that KCNQ1 mutations lead to down-regulation of Ca²⁺ channel inhibitory genes, with resultant increased I _Ca-L that underlies delayed repolarization in JLN. We further propose that diltiazem can be repurposed for treatment of patients with JLN.