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Brugada syndrome (BrS) is an inherited arrhythmogenic disease that may lead to sudden cardiac death in young adults with structurally normal hearts. No pharmacological therapy is available for BrS patients. This situation highlights the urgent need to overcome current difficulties by developing novel groundbreaking curative strategies. BrS has been associated with mutations in 18 different genes of which loss-of-function (LoF) CACNA1C mutations constitute the second most common cause. Here we tested the hypothesis that BrS associated with mutations in the CACNA1C gene encoding the L-type calcium channel (LTCC) pore-forming unit (Ca v α1.2) is functionally reverted by administration of a mimetic peptide (MP), which through binding to the LTCC chaperone beta subunit (Ca v β2) restores the physiological life cycle of aberrant LTCCs. Two novel Ca v α1.2 mutations associated with BrS were identified in young individuals. Transient transfection in heterologous and cardiac cells showed LoF phenotypes with reduced Ca 2+ current (I Ca ). In HEK293 cells overexpressing the two novel Ca v α1.2 mutations, Western blot analysis and cell surface biotinylation assays revealed reduced Ca v α1.2 protein levels at the plasma membrane for both mutants. Nano-BRET, Nano-Luciferase assays, and confocal microscopy analyses showed (i) reduced affinity of Ca v α1.2 for its Ca v β2 chaperone, (ii) shortened Ca v α1.2 half-life in the membrane, and (iii) impaired subcellular localization. Treatment of Ca v α1.2 mutant-transfected cells with a cell permeant MP restored channel trafficking and physiologic channel half-life, thereby resulting in I Ca similar to wild type. These results represent the first step towards the development of a gene-specific treatment for BrS due to defective trafficking of mutant LTCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Di Mauro, Ceriotti, Lodola, Salvarani, Modica, Bang, Mazzanti, Napolitano, Priori and Catalucci.)