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Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations.


ABSTRACT:

Background

The BAG3 (BLC2-associated athanogene 3) gene codes for an antiapoptotic protein located on the sarcomere Z-disc. Mutations in BAG3 are associated with dilated cardiomyopathy (DCM), but only a small number of cases have been reported to date, and the natural history of BAG3 cardiomyopathy is poorly understood.

Objectives

This study sought to describe the phenotype and prognosis of BAG3 mutations in a large multicenter DCM cohort.

Methods

The study cohort comprised 129 individuals with a BAG3 mutation (62% males, 35.1 ± 15.0 years of age) followed at 18 European centers. Localization of BAG3 in cardiac tissue was analyzed in patients with truncating BAG3 mutations using immunohistochemistry.

Results

At first evaluation, 57.4% of patients had DCM. After a median follow-up of 38 months (interquartile range: 7 to 95 months), 68.4% of patients had DCM and 26.1% who were initially phenotype-negative developed DCM. Disease penetrance in individuals >40 years of age was 80% at last evaluation, and there was a trend towards an earlier onset of DCM in men (age 34.6 ± 13.2 years vs. 40.7 ± 12.2 years; p = 0.053). The incidence of adverse cardiac events (death, left ventricular assist device, heart transplantation, and sustained ventricular arrhythmia) was 5.1% per year among individuals with DCM. Male sex, decreased left ventricular ejection fraction. and increased left ventricular end-diastolic diameter were associated with adverse cardiac events. Myocardial tissue from patients with a BAG3 mutation showed myofibril disarray and a relocation of BAG3 protein in the sarcomeric Z-disc.

Conclusions

DCM caused by mutations in BAG3 is characterized by high penetrance in carriers >40 years of age and a high risk of progressive heart failure. Male sex, decreased left ventricular ejection fraction, and enlarged left ventricular end-diastolic diameter are associated with adverse outcomes in patients with BAG3 mutations.

SUBMITTER: Dominguez F 

PROVIDER: S-EPMC6688826 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations.

Domínguez Fernando F   Cuenca Sofía S   Bilińska Zofia Z   Toro Rocío R   Villard Eric E   Barriales-Villa Roberto R   Ochoa Juan Pablo JP   Asselbergs Folkert F   Sammani Arjan A   Franaszczyk Maria M   Akhtar Mohammed M   Coronado-Albi Maria José MJ   Rangel-Sousa Diego D   Rodriguez-Palomares Jose F JF   Jiménez-Jáimez Juan J   Garcia-Pinilla José Manuel JM   Ripoll-Vera Tomás T   Mogollón-Jiménez Maria Victoria MV   Fontalba-Romero Ana A   Garcia-Medina Dolores D   Palomino-Doza Julian J   de Gonzalo-Calvo David D   Cicerchia Marcos M   Salazar-Mendiguchia Joel J   Salas Clara C   Pankuweit Sabine S   Hey Thomas Morris TM   Mogensen Jens J   Barton Paul J PJ   Charron Philippe P   Elliott Perry P   Garcia-Pavia Pablo P  

Journal of the American College of Cardiology 20181101 20


<h4>Background</h4>The BAG3 (BLC2-associated athanogene 3) gene codes for an antiapoptotic protein located on the sarcomere Z-disc. Mutations in BAG3 are associated with dilated cardiomyopathy (DCM), but only a small number of cases have been reported to date, and the natural history of BAG3 cardiomyopathy is poorly understood.<h4>Objectives</h4>This study sought to describe the phenotype and prognosis of BAG3 mutations in a large multicenter DCM cohort.<h4>Methods</h4>The study cohort comprised  ...[more]

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