Folate as a Potential Treatment for Lethal Ventricular Arrhythmias in TANGO2-Deficiency Disorder

Authors

Weiyi Xu
Yingqiong Cao
Sara B Stephens
Maria Jose Arredondo
Yifan Chen
William Perez
Liang Sun
Andy C Yu
Jean J Kim
Seema R Lalani
Na Li
Frank T Horrigan
Francisco Altamirano
Xander Ht Wehrens
Christina Y Miyake
Lilei Zhang

Publication Date

6-10-2024

Journal

JCI Insight

DOI

10.1172/jci.insight.171005

PMID

38855866

PMCID

PMC11382877

PubMedCentral® Posted Date

6-10-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Induced Pluripotent Stem Cells, Myocytes, Cardiac, Folic Acid, Arrhythmias, Cardiac, Male, Female, Child

Abstract

TANGO2-deficiency disorder (TDD) is an autosomal-recessive genetic disease caused by biallelic loss-of-function variants in the TANGO2 gene. TDD-associated cardiac arrhythmias are recalcitrant to standard antiarrhythmic medications and constitute the leading cause of death. Disease modeling for TDD has been primarily carried out using human dermal fibroblast and, more recently, in Drosophila by multiple research groups. No human cardiomyocyte system has been reported, which greatly hinders the investigation and understanding of TDD-associated arrhythmias. Here, we established potentially novel patient-derived induced pluripotent stem cell differentiated cardiomyocyte (iPSC-CM) models that recapitulate key electrophysiological abnormalities in TDD. These electrophysiological abnormalities were rescued in iPSC-CMs with either adenoviral expression of WT-TANGO2 or correction of the pathogenic variant using CRISPR editing. Our natural history study in patients with TDD suggests that the intake of multivitamin/B complex greatly diminished the risk of cardiac crises in patients with TDD. In agreement with the clinical findings, we demonstrated that high-dose folate (vitamin B9) virtually abolishes arrhythmias in TDD iPSC-CMs and that folate's effect was blocked by the dihydrofolate reductase inhibitor methotrexate, supporting the need for intracellular folate to mediate antiarrhythmic effects. In summary, data from TDD iPSC-CM models together with clinical observations support the use of B vitamins to mitigate cardiac crises in patients with TDD, providing potentially life-saving treatment strategies during life-threatening events.

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