Title

Decreased levels of BAG3 in a family with a rare variant and in idiopathic dilated cardiomyopathy.

Authors

Arthur M Feldman, Departments of Medicine Neuroscience Physiology and Pharmacology, Temple University School of Medicine
Rene L Begay, Cardiovascular Institute, Adult Medical Genetics Program, University of Colorado Health Sciences Center
Tijana Knezevic, Departments of Medicine Neuroscience Physiology and Pharmacology, Temple University School of Medicine
Valerie D Myers, Departments of Medicine Neuroscience Physiology and Pharmacology, Temple University School of Medicine
Dobromir B Slavov, Cardiovascular Institute, Adult Medical Genetics Program, University of Colorado Health Sciences Center
Weizhong Zhu, Departments of Medicine Neuroscience Physiology and Pharmacology, Temple University School of Medicine
Katherine Gowan, Cardiovascular Institute, Adult Medical Genetics Program, University of Colorado Health Sciences Center
Sharon L Graw, Cardiovascular Institute, Adult Medical Genetics Program, University of Colorado Health Sciences Center
Kenneth L Jones, Cardiovascular Institute, Adult Medical Genetics Program, University of Colorado Health Sciences Center
Douglas G Tilley, Departments of Medicine Neuroscience Physiology and Pharmacology, Temple University School of Medicine
Ryan C Coleman, Departments of Medicine Neuroscience Physiology and Pharmacology, Temple University School of Medicine
Paul Walinsky, Division of Cardiology, Department of Medicine, Thomas Jefferson UniversityFollow
Joseph Y Cheung, Departments of Medicine Neuroscience Physiology and Pharmacology, Temple University School of Medicine
Luisa Mestroni, Cardiovascular Institute, Adult Medical Genetics Program, University of Colorado Health Sciences Center
Kamel Khalili, Departments of Medicine Neuroscience Physiology and Pharmacology, Temple University School of Medicine
Mathew R G Taylor, Cardiovascular Institute, Adult Medical Genetics Program, University of Colorado Health Sciences Center; Cardiovascular Institute, University of Colorado Denver

Document Type

Article

Publication Date

11-1-2014

Comments

This article has been peer reviewed. It was published in: Journal of Cellular Physiology.

Volume 229, Issue 11, November 2014, Pages 1697-1702.

The published version is available at DOI: 10.1002/jcp.24615

Copyright © 2014 Wiley Periodicals, Inc.

Abstract

The most common cause of dilated cardiomyopathy and heart failure (HF) is ischemic heart disease; however, in a third of all patients the cause remains undefined and patients are diagnosed as having idiopathic dilated cardiomyopathy (IDC). Recent studies suggest that many patients with IDC have a family history of HF and rare genetic variants in over 35 genes have been shown to be causative of disease. We employed whole-exome sequencing to identify the causative variant in a large family with autosomal dominant transmission of dilated cardiomyopathy. Sequencing and subsequent informatics revealed a novel 10-nucleotide deletion in the BCL2-associated athanogene 3 (BAG3) gene (Ch10:del 121436332_12143641: del. 1266_1275 [NM 004281]) that segregated with all affected individuals. The deletion predicted a shift in the reading frame with the resultant deletion of 135 amino acids from the C-terminal end of the protein. Consistent with genetic variants in genes encoding other sarcomeric proteins there was a considerable amount of genetic heterogeneity in the affected family members. Interestingly, we also found that the levels of BAG3 protein were significantly reduced in the hearts from unrelated patients with end-stage HF undergoing cardiac transplantation when compared with non-failing controls. Diminished levels of BAG3 protein may be associated with both familial and non-familial forms of dilated cardiomyopathy.