Multiomic and electrophysiologic analyses reveal that an inherited MRC2 variant causes fibroblast dysfunction and increased atrial fibrillation susceptibility

A recent study identified a rare variant in the mannose receptor C type 2 (<i>MRC2</i>) gene in individuals with familial reentrant supraventricular tachycardia, a Wolff-Parkinson-White (WPW) electrocardiogram pattern, and structurally normal hearts. WPW syndrome is associated with atrial fibrillation (AF), and <i>MRC2</i> was recently proposed as a protective gene for AF. We determined whether the E990G-heterozygous (het) loss-of-function variant in <i>Mrc2</i> increases AF susceptibility and identified aberrant cellular mechanisms resulting from <i>Mrc2</i> deficiency in atrial cardiofibroblasts (ACFs) and atrial tissue in mice that may promote AF. Programmed electrical stimulation was performed to determine AF susceptibility in <i>Mrc2</i> E990G-het mice and wild-type (WT) controls. ACFs were isolated from these mice and cultured, and transcriptomic profiling by RNA sequencing and secretomic/proteomic profiling by mass spectrometry were performed on ACFs and whole atrial tissue. E990G-het mice exhibited increased susceptibility to pacing-induced AF and had decreased atrioventricular effective refractory periods compared with WT controls. Transcriptomic, secretomic, and proteomic profiling of cultured ACFs and whole atrial tissue revealed differential expression of several fibrotic regulators in E990G-het versus WT mice, including decreased ACF expression of matrix metalloproteinase 13, which degrades collagen types I, II, and III; decreased ACF expression and secretion of matrix metalloproteinase 12, which degrades collagen types I, III, IV, elastin, and fibronectin; and increased tissue levels of cellular communication network factor 2/connective tissue growth factor, a profibrotic regulator. In conclusion, <i>Mrc2</i> E990G-het mice exhibit increased AF susceptibility and differentially regulated fibrotic genes and proteins.<b>NEW & NOTEWORTHY</b> Our study reveals a rare MRC2 gene variant (E990G) linked to familial supraventricular tachycardia and Wolff-Parkinson-White syndrome increases atrial fibrillation (AF) susceptibility in mice. The E990G-heterozygous variant disrupts atrial cardiofibroblast function, reducing protective matrix metalloproteinases (MMP-12 and MMP-13) and elevating profibrotic CCN2/CTGF levels, as shown through transcriptomic and proteomic profiling. This suggests that MRC2 deficiency promotes AF by altering fibrotic regulation in atrial tissue.