Key result
Reduced cardiac expression of Vps34 was identified in a subset of HCM patients, and muscle-specific loss of Vps34 in mice led to HCM-like manifestations, sudden death, and CryAB aggregate accumulation.
Disruption of the Vps34-CryAB axis represents a novel potential etiology for hypertrophic cardiomyopathy.
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May refine subset-specific HCM prognostication; leaves open whether Vps34 modulation alters human disease course.
Hypertrophic cardiomyopathy (HCM) is a common heart disease with a prevalence of 1 in 500 in the general population. Several mutations in genes encoding cardiac proteins have been found in HCM patients, but these changes do not predict occurrence or prognosis and the molecular mechanisms underlying HCM remain largely elusive. Here we show that cardiac expression of vacuolar protein sorting 34 (Vps34) is reduced in a subset of HCM patients. In a mouse model, muscle-specific loss of Vps34 led to HCM-like manifestations and sudden death. Vps34-deficient hearts exhibited abnormal histopathologies, including myofibrillar disarray and aggregates containing αB-crystallin (CryAB). These features result from a block in the ESCRT-mediated proteolysis that normally degrades K63-polyubiquitinated CryAB. CryAB deposition was also found in myocardial specimens from a subset of HCM patients whose hearts showed decreased Vps34. Our results identify disruption of the previously unknown Vps34-CryAB axis as a potentially novel etiology of HCM.
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Kimura et al. (2017) studied Hypertrophic cardiomyopathy (n=45). Reduced Vps34 expression vs. Normal Vps34 expression was evaluated on Vps34 protein expression and presence of CryAB aggregates. Reduced cardiac expression of Vps34 was identified in a subset of HCM patients, and muscle-specific loss of Vps34 in mice led to HCM-like manifestations, sudden death, and CryAB aggregate accumulation.
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