Dilated cardiomyopathy-associatedBAG3mutations impair Z-disc assembly and enhance sensitivity to apoptosis in cardiomyocytes

Abstract

Dilated cardiomyopathy (DCM) is characterized by dilation of left ventricular cavity with systolic dysfunction. Clinical symptom of DCM is heart failure, often associated with cardiac sudden death. About 20-35% of DCM patients have apparent family histories and it has been revealed that mutations in genes for sarcomere proteins cause DCM. However, the disease-causing mutations can be found only in about 17% of Japanese patients with familial DCM. Bcl-2-associated athanogene 3 (BAG3) is a co-chaperone protein with antiapoptotic function, which localizes at Z-disc in the striated muscles. Recently, BAG3 gene mutations in DCM patients were reported, but the functional abnormalities caused by the mutations are not fully unraveled. In this study, we analyzed 72 Japanese familial DCM patients for mutations in BAG3 and found two mutations, p.Arg218Trp and p.Leu462Pro, in two cases of adult-onset DCM without skeletal myopathy, which were absent from 400 control subjects. Functional studies at the cellular level revealed that the DCM-associated BAG3 mutations impaired the Z-disc assembly and increased the sensitivities to stress-induced apoptosis. These observations suggested that BAG3 mutations present in 2.8% of Japanese familial DCM patients caused DCM possibly by interfering with Z-disc assembly and inducing apoptotic cell death under the metabolic stress.

Dilated Cardiomyopathy-Associated <i>FHOD3</i> Variant Impairs the Ability to Induce Activation of Transcription Factor Serum Response Factor

“…The diagnostic criteria for DCM have been described previously. 12 The patients had been analyzed for mutations in the known cardiomyopathy-associated genes, and none was found in any of them, although the largest gene in humans, the titin gene (TTN) consisting or more that 360 exons, was analyzed for approximately 30% of the gene region. 13 As controls, we included 400 healthy Japanese individuals.…”

Myofibrillar Myopathies and the Z-Disk Associated Proteins

“…Nondenaturing gel electrophoresis revealed faster migration of the mutant BAG3 complex than wildtype [13], suggesting that the loss of function may be due to reduced interaction with partner proteins, possibly Bcl-2, given that an increase in apoptosis is observed. This is supported by transfection of P209L mutant BAG3 into neonatal cardiomyocytes resulting in increased susceptibility to stress mediated apoptosis [226] and the observation that mice deficient in BAG3 also display increased apoptosis [228]. It has been shown that the downregulation of BAG3 enhances the apoptotic response to chemotherapy in lymphocytic leukaemia cells making it a potential target for cancer therapies [248], and further demonstrating its anti-apoptotic role.…”

“…Since then 10 additional Bag3 mutations have been reported of which nine result in DCM [225,226] and one in MFM [227] (Table 7). BAG3 is one of six members of the BAG family of proteins.…”

“…Other studies: neonatal rat cardiomyocytes showed problems in cell fusion; COS-7 cells presented granules in their cytoplasm; C2C12 with reduced BAG3 protein levels show increased apoptosis. Classified as MFM [13,226,228,240] c.625C>T + c.772C>T…”

“…Other studies: neonatal rat cardiomyocytes presented abnormal Z-disk assembly and increased susceptibility to apoptosis. Classified as DCM [226] c.1430G>A…”