Familial Dilated Cardiomyopathy Caused by a Novel Frameshift in the BAG3 Gene

Abstract

BackgroundDilated cardiomyopathy, a major cause of chronic heart failure and cardiac transplantation, is characterized by left ventricular or biventricular heart dilatation. In nearly 50% of cases the pathology is inherited, and more than 60 genes have been reported as disease-causing. However, in 30% of familial cases the mutation remains unidentified even after comprehensive genetic analysis. This study clinically and genetically assessed a large Spanish family affected by dilated cardiomyopathy to search for novel variations.Methods and ResultsOur study included a total of 100 family members. Clinical assessment was performed in alive, and genetic analysis was also performed in alive and 1 deceased relative. Genetic screening included resequencing of 55 genes associated with sudden cardiac death, and Sanger sequencing of main disease-associated genes. Genetic analysis identified a frame-shift variation in BAG3 (p.H243Tfr*64) in 32 patients. Genotype-phenotype correlation identified substantial heterogeneity in disease expression. Of 32 genetic carriers (one deceased), 21 relatives were clinically affected, and 10 were asymptomatic. Seventeen of the symptomatic genetic carriers exhibited proto-diastolic septal knock by echocardiographic assessment.ConclusionsWe report p.H243Tfr*64_BAG3 as a novel pathogenic variation responsible for familial dilated cardiomyopathy. This variation correlates with a more severe phenotype of the disease, mainly in younger individuals. Genetic analysis in families, even asymptomatic individuals, enables early identification of individuals at risk and allows implementation of preventive measures.

An interaction study in mammalian cells demonstrates weak binding of HSPB2 to BAG3, which is regulated by HSPB3 and abrogated by HSPB8

“…In the present study, we compared the binding affinity to BAG3 of several HSPB members upon overexpression in HEK293T cells. Since BAG3 is highly expressed in cardiac and skeletal muscle cells and its mutations leads to cardiomyopathy and muscular dystrophy (Selcen, Muntoni et al 2009;Arimura, Ishikawa et al 2011;Norton, Li et al 2011;Villard, Perret et al 2011;Chami, Tadros et al 2014;Franaszczyk, Bilinska et al 2014;Toro, Perez-Serra et al 2016), we selected for our study the HSPB proteins that are expressed in skeletal and/or cardiac muscle cells, namely HSPB1, HSPB2, HSPB3, HSPB6, HSPB7, and HSPB8 (Fontaine, Sun et al 2005). We mainly used V5-tagged forms of these HSPBs in order to directly compare their expression levels and their binding affinities to BAG3, using an antibody specific for the V5 tag.…”

Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report

“…Non‐desmosomal pathogenic variants are described in DES, LMNA, SCN5A, CDH2, CTNNA3, FLNC, PLN, TGFB3, TMEM43, RYR2 , TJP1 and TTN and reports describe a disproportionately high burden of ventricular arrhythmia in dilated cardiomyopathy caused by pathogenic variants in RBM20 , TNNT2 , and BAG3 . The possible relation between the main causative genes and the relative involvement of the left and right ventricles are shown in Table …”

Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy

“…8,[10][11][12][13][14][15][16][17][18][19][20] Although we made a genetic analysis of several cardiac core transcriptional factor genes in the two mutation carriers with DCM, including GATA4, GATA5, GATA6, TBX5, TBX20, and HAND1, as described previously, [22][23][24][25][26][27][28][29][30][31] and found no mutations, we cannot rule out the possibility that the genetic variants in other genes may also contribute to DCM in these two patients. Genome sequencing analysis may help to explain the possibility for these patients.…”

“…8,9) At present, an increasing number of causative mutations in > 50 genes have been causally linked to idiopathic DCM. 8,[10][11][12][13][14][15][16][17][18][19][20] Among these well established DCM-associated genes, most encode contractile sarcomeric proteins as well as cytoskeletal/sarcolemmal and nuclear envelope proteins. 8) Nevertheless, these DCM-causing genes can explain only about one-third of patients and for most genes, the mutational frequency is low, with genetic mutation occurring in < 1% of DCM patients.…”