A Zebrafish Model of Human Barth Syndrome Reveals the Essential Role of Tafazzin in Cardiac Development and Function

Barth syndrome is an X-linked disorder characterized by cardiomyopathy, skeletal myopathy, neutropenia, organic aciduria, and growth retardation caused by mutations in tafazzin. The sequence similarity of tafazzin to acyltransferases suggests a role in mitochondrial phospholipid metabolism. To study...

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Bibliographic Details
Published in:Circulation research 2006-07, Vol.99 (2), p.201-208
Main Authors: Khuchua, Zaza, Yue, Zou, Batts, Lorene, Strauss, Arnold W
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cardiology. Vascular system
Cardiomyopathy, Dilated - congenital
Cardiomyopathy, Dilated - etiology
Cardiomyopathy, Dilated - genetics
Child Development
Disease Models, Animal
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation, Developmental
Heart
Heart - growth & development
Heart - physiology
Humans
Infant
Medical sciences
Myocarditis. Cardiomyopathies
RNA, Antisense - pharmacology
RNA, Messenger - antagonists & inhibitors
Syndrome
Transcription Factors - deficiency
Transcription Factors - genetics
Transcription Factors - physiology
Vertebrates: cardiovascular system
Zebrafish
Zebrafish Proteins - deficiency
Zebrafish Proteins - genetics
Zebrafish Proteins - physiology
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Summary:Barth syndrome is an X-linked disorder characterized by cardiomyopathy, skeletal myopathy, neutropenia, organic aciduria, and growth retardation caused by mutations in tafazzin. The sequence similarity of tafazzin to acyltransferases suggests a role in mitochondrial phospholipid metabolism. To study the role of tafazzin in heart function and development, we created a knockdown zebrafish model. Zebrafish tafazzin mRNA is first evident at 7 hours post-fertilization (hpf). At 10 and 24 hpf, tafazzin mRNA is ubiquitous, with highest levels in the head. By 51 hpf, expression becomes cardiac restricted. The tafazzin knockdown created by antisense morpholino yolk injection resulted in dose-dependent lethality, severe developmental and growth retardation, marked bradycardia and pericardial effusions, and generalized edema, signs that resemble human Barth syndrome heart failure. This knockdown phenotype was rescued by concomitant injection of normal tafazzin mRNA. Abnormal cardiac development, with a linear, nonlooped heart, and hypomorphic tail and eye development proves that tafazzin is essential for overall zebrafish development, especially of the heart. The tafazzin knockdown zebrafish provides an animal model similar to Barth syndrome to analyze the severity of human mutants and to test potential treatments.
ISSN:0009-7330
1524-4571
DOI:10.1161/01.RES.0000233378.95325.ce