Key result
The ARVC-associated DSG2-p.R46Q variation demonstrated impaired prodomain cleavage and significantly increased cellular adhesion (ratio 2.29 vs 1.25, p<0.0001) compared to wild-type DSG2.
Population
In vitro model using human fibrosarcoma cell line HT1080 expressing extracellular domains and full-length…
Comparison
Expression of ARVC-associated DSG2 missense… vs Expression of wild-type DSG2 protein
Design
Preclinical
Authors
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Does not yet inform ARVC management; leaves open gain-of-function role of DSG2 variants in humans.
Absolute Event Rate: 2.29% vs 1.25%
p-value: p=<0.0001
The ARVC-associated DSG2-p.R46Q variation impairs prodomain cleavage and alters cellular adhesion, suggesting a gain-of-function mechanism, while other predicted damaging variants showed no functional effects in this model.
Gaertner et al. (2012) studied Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). DSG2-p.R46Q variant vs. Wild-type DSG2 was evaluated on Ratio of rECD-binding to HT1080 cells (cellular adhesion) (p=<0.0001). The ARVC-associated DSG2-p.R46Q variation demonstrated impaired prodomain cleavage and significantly increased cellular adhesion (ratio 2.29 vs 1.25, p<0.0001) compared to wild-type DSG2.
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