Key result
Diminished Wt1 improved slowed cardiac conduction in a challenged mouse model, and WT1 overexpression in hiPSC-derived cardiomyocytes reduced sodium current density, linking WT1 to Brugada syndrome.
Why the study?
A recent GWAS implicated a chromosome 11 genomic region overlapping transcription factor WT1 in Brugada syndrome susceptibility, prompting investigation into the role of WT1 in cardiac conduction.
Does WT1 modulation affect SCN5A expression and cardiac conduction in preclinical models of Brugada syndrome?
Does WT1 modulation affect SCN5A expression and cardiac conduction in preclinical models of Brugada syndrome?
WT1 is identified as a novel contributor to Brugada syndrome pathophysiology, where increased WT1 expression reduces SCN5A expression and sodium current density, impairing cardiac conduction.
Answers are grounded in this paper and cite their sources.
WT1 modulation improves conduction in preclinical Brugada models; hypothesis-generating, leaves open clinical relevance.
Brugada syndrome (BrS) is an inherited cardiac arrhythmic disorder caused by conduction slowing primarily affecting the right ventricular (RV) outflow tract (RVOT). A recent genome-wide association study (GWAS) implicated a genomic region in chromosome 11, overlapping the transcription factor WT1 , in BrS susceptibility. Here, we investigated the role of WT1 on cardiac conduction using a heterozygous knockout mouse model ( Wt1 +/- ). Transcriptomic analysis revealed increased Scn5a predominantly in Wt1 +/- cardiomyocytes located subepicardially in the RV and RVOT without any changes in electrical properties. To unmask an effect on cardiac conduction, we performed optical mapping in a severely challenged setting offered by Scn5a haploinsufficiency, ageing, and exposure to the sodium channel blocker ajmaline and found that diminished Wt1 improved the observed slowed conduction. Examination of human single-nuclei cardiac datasets indicated a strong negative correlation between WT1 and SCN5A expression. In line with this observation, cardiac samples from patients carrying mutations in SCN5A showed increased WT1 protein abundance in histological sections, suggesting that increased WT1 , and not loss, is associated with BrS pathophysiology. By deleting the mouse orthologue of a BrS-associated noncoding region (RE) harboring a candidate regulatory element, we established that this RE controls expression of Wt1 specifically in the (sub)epicardium of the RV. Lastly, transient overexpression of WT1 in hiPSC-derived cardiomyocytes resulted in notably reduced sodium current density. Our study thereby identifies the transcription factor WT1 as a novel contributor to the pathophysiology of BrS, at least in part, through SCN5A .
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Marsman et al. (2025) studied Brugada syndrome. WT1 gene alteration vs. Wild-type / control was evaluated on Cardiac conduction and SCN5A expression / sodium current density. Diminished Wt1 improved slowed cardiac conduction in a challenged mouse model, and WT1 overexpression in hiPSC-derived cardiomyocytes reduced sodium current density, linking WT1 to Brugada syndrome.
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