Genetic defects in a His-Purkinje system transcription factor,IRX3, cause lethal cardiac arrhythmias

Abstract

IRX3 genetic defects and resultant functional perturbation in the His-Purkinje system are novel genetic risk factors of idiopathic VF, and would improve risk stratification and preventive therapy for SCD in otherwise healthy hearts.

The formation and function of the cardiac conduction system

“…The homeobox transcription factor Irx3 is expressed in the trabecular ventricular myocardium and its expression becomes confined to the VCS (Christoffels et al, 2000;Zhang et al, 2011). Here, Irx3 directly supresses Cx43 and (indirectly) activates Cx40 and Scn5a (Zhang et al, 2011;Koizumi et al, 2015). Irx3 mutant mice develop delayed ventricular activation and abnormal conduction (Zhang et al, 2011) and ventricular arrhythmias (Koizumi et al, 2015).…”

“…Here, Irx3 directly supresses Cx43 and (indirectly) activates Cx40 and Scn5a (Zhang et al, 2011;Koizumi et al, 2015). Irx3 mutant mice develop delayed ventricular activation and abnormal conduction (Zhang et al, 2011) and ventricular arrhythmias (Koizumi et al, 2015). In humans, sequence analysis of IRX3 exons in 130 probands of idiopathic ventricular fibrillation revealed two novel IRX3 mutations (Koizumi et al, 2015).…”

“…Irx3 mutant mice develop delayed ventricular activation and abnormal conduction (Zhang et al, 2011) and ventricular arrhythmias (Koizumi et al, 2015). In humans, sequence analysis of IRX3 exons in 130 probands of idiopathic ventricular fibrillation revealed two novel IRX3 mutations (Koizumi et al, 2015). The related factor Irx5 is expressed in the endocardium and subendocardial myocytes (including the layer that will form the Purkinje fibres) where it represses, amongst others, the transient outward potassium current (I to ) (Costantini et al, 2005).…”

Idiopathic Ventricular Fibrillation

“…17,18 The pathogenesis of short-coupled VPBs is largely unknown, although a genetic origin is detected in a limited number of patients with scTdP/VF including the Dutch DPP6-haplotype, a novel RyR mutation that causes scTdP in rest, and a novel IRX3 mutation. 10,19,20 Until the pathogenesis is further specified, scTdP/VF remains a subgroup of IVF because no particular phenotype responsible for VF can be detected either on the ECG nor during additional diagnostic testing.…”

“…First, IVF might have a monogenic origin. 10,19,20 Second, the origin could be polygenic. Third, the origin might be multifactorial in which mono-or polygenic mutations need particular environmental and discrete subclinical structural abnormalities, for example minimal electrolyte disturbances such as a mild hypokalemia or development of small areas of fibrotic myocardial tissue, that are currently undetectable with the available diagnostic modalities.…”