Variant Intronic Enhancer Controls SCN10A-short Expression and Heart Conduction

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Ion Channel Physiology

Background:

• SCN10A genetic variants are linked to cardiac arrhythmias like atrial fibrillation and Brugada syndrome.
• The precise cardiac function of SCN10A and its associated sodium channel Na_V1.8 remains unclear.
• This study investigates cardiac SCN10A expression and the role of a regulatory enhancer element.

Purpose of the Study:

• To determine the cardiac expression pattern of SCN10A.
• To elucidate the function of a variant-sensitive intronic enhancer regulating SCN10A.
• To understand how genetic variations in this enhancer affect cardiac function and rhythm.

Main Methods:

• Investigated SCN10A expression in mouse and human heart tissues.
• Utilized CRISPR/Cas9 to disrupt the intronic enhancer in mice, followed by transcriptomic and electrophysiological analysis.
• Performed genome-wide association studies and expression quantitative trait loci analysis to link genetic variants to gene expression.

Main Results:

• Identified a cardiac-specific short SCN10A transcript (Scn10a-short) in atrial and nodal cardiomyocytes, transcribed from an intronic enhancer-promoter.
• Disruption of the enhancer in mice reduced Scn10a-short expression, leading to impaired atrial conduction, arrhythmias, and altered sodium current.
• Scn10a-short expression enhanced Na_V1.5-mediated sodium current, while Scn5a expression remained unaffected.

Conclusions:

• Genetic variants near SCN10A modulate enhancer activity, controlling the expression of a cardiac-specific SCN10A-short transcript.
• This noncoding variation impacts Na_V1.5 function and cardiac electrophysiology, influencing arrhythmia susceptibility.
• The study reveals a novel mechanism where SCN10A variants affect heart rhythm through regulation of a functional portion of Na_V1.8 in cardiomyocytes.