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Cav1.2 (CACNA1C) is one of the most important proteins in cardiomyocyte physiology and excitation-contraction coupling representing a critical subunit of the L-type calcium channel. Mutations in Cav1.2 have been linked to Brugada syndrome. Clinically, Brugada syndrome can present as abnormal heart rhythm, syncope, and sudden cardiac death; however, some individuals with the disorder do not display any symptoms.
A loss-of-function missense mutation in the gene encoding Cav1.2 (CACNA1C) gives rise to Brugada syndrome Type 3 (BrS3) resulting in a change of amino acid 490 from glycine-to-arginine (G490R). The pathobiology of this mutation remains generally poorly understood.
To enable investigation of the functional consequences of the mutation, the G490R mutation was engineered from an apparently healthy, normal donor with no known disease-related genotypes. The use of genome engineering strategies to generate this mutation results in an isogenic pair that is vital for analysis.
MyCell® Cardiomyocytes (G490R) display the abnormal function and sensitivity to calcium channel modulators consistent with BrS3 that results from a loss-of-function mutation in the L-type calcium channel.
MyCell Cardiomyocytes (G490R) and its isogenic control (iCell® Cardiomyocytes, 01434) exhibit the relevant biology and functionality to advance research and preclinical studies for Brugada syndrome.
Contractility was monitored by measuring impedance over time using the xCELLigence CardioECR (ACEA Biosciences). MyCell Cardiomyocytes (G490R) display reduced contraction amplitude and increased beat rate compared to the isogenic control. (DIV 14)
Contractility and electrophysiology were monitored using the xCELLigence CardioECR (ACEA Biosciences). MyCell Cardiomyocytes (G490R) display reduced sensitivity to calcium channel agonist BayK 8466 compared to the isogenic control. (DIV 14, 30 minutes after treatment)
Contractility and electrophysiology were monitored using the xCELLigence CardioECR (ACEA Biosciences). MyCell Cardiomyocytes (G490R) display increased sensitivity to a calcium channel blocker of the dihydropyridine class compared to the isogenic control. (DIV 14, 30 minutes after treatment) Q = quiescence.