The BAG3 gene variants in Polish patients with dilated cardiomyopathy: four novel mutations and a genotype-phenotype correlation

Abstract

BackgroundBAG3 gene mutations have been recently implicated as a novel cause of dilated cardiomyopathy (DCM). Our aim was to evaluate the prevalence of BAG3 mutations in Polish patients with DCM and to search for genotype-phenotype correlations.MethodsWe studied 90 unrelated probands by direct sequencing of BAG3 exons and splice sites. Large deletions/insertions were screened for by quantitative real time polymerase chain reaction (qPCR).ResultsWe found 5 different mutations in 6 probands and a total of 21 mutations among their relatives: the known p.Glu455Lys mutation (2 families), 4 novel mutations: p.Gln353ArgfsX10 (c.1055delC), p.Gly379AlafsX45 (c.1135delG), p.Tyr451X (c.1353C>A) and a large deletion of 17,990 bp removing BAG3 exons 3–4. Analysis of mutation positive relatives of the probands from this study pooled with those previously reported showed higher DCM prevalence among those with missense vs. truncating mutations (OR = 8.33, P = 0.0058) as well as a difference in age at disease onset between the former and the latter in Kaplan-Meier survival analysis (P = 0.006). Clinical data from our study suggested that in BAG3 mutation carriers acute onset DCM with hemodynamic compromise may be triggered by infection.ConclusionsBAG3 point mutations and large deletions are relatively frequent cause of DCM. Delayed DCM onset associated with truncating vs. non-truncating mutations may be important for genetic counseling.

A BAG3 chaperone complex maintains cardiomyocyte function during proteotoxic stress

“…Our approach, however, allows the direct comparison of different mutations in a single isogenic background, which will be crucial for further dissecting mechanisms that correlate genotype and phenotype, as seen with BAG3. Indeed, missense mutations in conserved domains of the BAG3 protein cause different, although severe, clinical phenotypes (4,11). In future studies we hope to characterize the functional effects of missense mutations in key protein-protein interaction domains.…”

“…For example, the rare P209L missense mutation causes severe childhood-onset myofibrillar myopathy, a lethal disease that affects both skeletal and cardiac muscle, possibly through a toxic gain of function in the BAG3 protein (4,6,7). Additionally, a variety of heterozygous mutations in BAG3, many of which are nonsense or frameshift mutations consistent with loss of function, cause autosomal dominant familial dilated cardiomyopathy (8)(9)(10)(11). BAG3 has also been associated with acquired forms of cardiomyopathy, such as stress (Takotsubo) cardiomyopathy (12)(13)(14).…”

Truncating mutations on myofibrillar myopathies causing genes as prevalent molecular explanations on patients with dilated cardiomyopathy

“…[19][20][21][22][23] Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid anti-apoptotic protein that is constitutively expressed in the heart. [19][20][21][22][23] Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid anti-apoptotic protein that is constitutively expressed in the heart.…”

BAG3 regulates contractility and Ca2+ homeostasis in adult mouse ventricular myocytes

“…However, several findings suggest that BAG3 may play a larger role in myocardial biology. For example, disruption of myofibril structures was not a ubiquitous finding in patients with mutations in BAG3 and idiopathic dilated cardiomyopathy [13], and giant axonal neuropathy and neural conduction velocity slowing were found in affected members of a family with a BAG3 mutation and hypertrophic cardiomyopathy [14]. Therefore, the current study was undertaken to test the hypothesis that BAG3 can influence myocyte contractility in adult cardiac myocytes.…”