The R120G knock-in mutation in αB-crystallin is insufficient to induce cardiomyopathy in mice

Alpha B-crystallin (CryAB) is a small heat-shock protein highly expressed in cardiac tissue, where it functions as a molecular chaperone that helps prevent protein aggregation, particularly under stress conditions. A missense mutation in CryAB (R120G) causes autosomal dominant cardiomyopathy in humans and is characterized by extensive protein aggregation in cardiomyocytes. To better understand the pathogenic mechanisms underlying CryAB^R120G-associated cardiomyopathy, appropriate in vivo models are essential. Genetic mouse models are valuable tools for investigating disease pathogenesis and evaluating potential therapeutic strategies. In this study, we characterized a homozygous CryAB^R120G knock-in (KI) mouse model to assess the impact of this mutation on cardiac function. CryAB^R120G KI mice exhibited no overt changes in cardiac structure and function up to 12 mo of age, with minimal changes in cardiac and proteotoxic stress markers, except for increased atrial natriuretic peptide expression at 12 mo. Protein quality control pathways remained largely unchanged. Although mitochondrial respiration was normal in young CryAB^R120G KI mice, it was reduced at 12 mo of age. Despite the presence of insoluble protein aggregates, homozygous CryAB^R120G KI mice did not develop overt structural or functional cardiomyopathy through 12 mo of age. These findings indicate that, within the age range examined, the CryAB^R120G KI model does not reproduce the overt cardiomyopathic phenotype associated with the CRYAB^R120G mutation in patients.NEW & NOTEWORTHY This study demonstrates that homozygous CryAB^R120G knock-in mice fail to develop overt cardiomyopathy despite the accumulation of insoluble protein aggregates. Thus, within the age range examined, this mouse model does not reproduce the cardiomyopathic phenotype associated with the CRYABR120G mutation in patients. These findings underscore the importance of validating genetic mouse models, as they may incompletely reflect the pathophysiological mechanisms and disease progression observed in humans.