title: A zebrafish model of human Barth syndrome reveals the essential role of tafazzin in cardiac development and function.
abstract: 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.
authors.affiliation: Vanderbilt Children's Hospital and Vanderbilt University Medical Center, Rm B-3307 MCN, 1161 21st Ave S, Nashville, Tennessee 37232, USA. zaza.khuchua@vanderbilt.edu
authors.forename: Zaza
authors.initials: Z
authors.lastname: Khuchua
authors.forename: Zou
authors.initials: Z
authors.lastname: Yue
authors.forename: Lorene
authors.initials: L
authors.lastname: Batts
authors.forename: Arnold W
authors.initials: AW
authors.lastname: Strauss
mesh_terms: D000217:Acyltransferases; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000151:congenital* / Q000209:etiology* / Q000235:genetics; D002657:Child Development; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000254:growth & development* / Q000502:physiology; D006801:Humans; D007223:Infant; D016372:RNA, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D013577:Syndrome; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: D016372:RNA, Antisense; D012333:RNA, Messenger; D014157:Transcription Factors; D029961:Zebrafish Proteins; D000217:Acyltransferases; C512741:tafazzin protein, zebrafish