Metabolic crisis and TRPM4 activation cause QT prolongation in TANGO2 deficiency disorder

AIMS: TANGO2 deficiency disorder (TDD), caused by homozygous large deletions in TANGO2, is associated with impaired fatty acid oxidation and metabolic crises that frequently trigger QT prolongation and arrhythmias. The objective was to study the mechanisms responsible for QT prolongation and arrhythmogenesis in TDD. METHODS AND RESULTS: CRISPR/Cas9 were used to generate human induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) carrying a TANGO2 exon 3-9 deletion (TANGO2-/-). Bioenergetic function (mitochondrial oxygen consumption rate, intracellular ATP/ADP ratio) and action potentials (APs) were studied under glucose- or palmitate-fueled conditions.This study reports a TDD clinical case of QT prolongation and arrhythmia that responded favorably to L-type calcium channel (LTCC) inhibition with verapamil or vitamin B-complex supplementation. The mechanisms underlying clinical presentations and therapeutic responses were investigated using TANGO2-/- hiPSC-CMs. In glucose-containing medium, the bioenergetic function was comparable between control and TANGO2-/- hiPSC-CMs. In contrast, using palmitate as energy substrate triggered a profound reduction in cellular ATP production rate and decreased ATP/ADP ratios in TANGO2-/- hiPSC-CMs, exacerbated by 24-hour fasting. This crisis was prevented by 2-week treatment with vitamins B5 and B9. During the crisis, TANGO2-/- hiPSC-CMs exhibited AP prolongation, prevented by intracellular delivery of Mg-ATP or creatine kinase. LTCC inhibition with verapamil prevented AP prolongation by normalizing ATP/ADP ratios and intracellular Ca mishandling. Importantly, the metabolic crisis upregulated TRPM4, an ATP- and Ca-regulated channel. TRPM4 siRNA knockdown or pharmacological block prevented AP prolongation without rescuing the energetic deficit of TANGO2-/- hiPSC-CMs. CONCLUSION: These findings suggest a mechanistic link between ATP deficiency, TRPM4 activation, and AP prolongation in TDD. Targeting TRPM4 therapeutically may help prevent QT prolongation and cardiac arrhythmias in TDD crisis.