A Drosophila model of Barth syndrome.
Barth syndrome is an X-linked disease presenting with cardiomyopathy and skeletal muscle weakness. It is caused by mutations in tafazzin, a putative acyl transferase that has been associated with altered metabolism of the mitochondrial phospholipid cardiolipin. To investigate the molecular basis of Barth syndrome, we created Drosophila melanogaster mutants, resulting from imprecise excision of a P element inserted upstream of the coding region of the tafazzin gene. Homozygous flies for that mutation were unable to express the full-length isoform of tafazzin, as documented by RNA and Western blot analysis, but two shorter tafazzin transcripts were still present, although the expression levels of their encoded proteins were too low to be detectable by Western blotting. The tafazzin mutation caused an 80% reduction of cardiolipin and a diversification of its molecular composition, similar to the changes seen in Barth patients. Other phospholipids, like phosphatidylcholine and phosphatidylethanolamine, were not affected. Flies with the tafazzin mutation showed a reduced locomotor activity, measured in flying and climbing assays, and their indirect flight muscles displayed frequent mitochondrial abnormalities, mostly in the cristae membranes. Thus, tafazzin mutations in Drosophila generated a Barth-related phenotype, with the triad of abnormal cardiolipin, pathologic mitochondria, and motor weakness, suggesting causal links between these findings. We conclude that a lack of full-length tafazzin is responsible for the cardiolipin deficiency, which is integral to the disease mechanism, leading to mitochondrial myopathy.
Xu
Yang
Y
Department of Anesthesiology, New York University School of Medicine, New York, NY 10016, USA.
Condell
Morgan
M
Plesken
Heide
H
Edelman-Novemsky
Irit
I
Ma
Jinping
J
Ren
Mindong
M
Schlame
Michael
M
D008243:1-Acylglycerophosphocholine O-Acyltransferase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D002308:Cardiolipins / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000502:physiology; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017240:Mitochondrial Myopathies / Q000235:genetics / Q000503:physiopathology; D009043:Motor Activity / Q000502:physiology; D018482:Muscle, Skeletal / Q000002:abnormalities / Q000502:physiology / Q000648:ultrastructure; D010713:Phosphatidylcholines / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D002308:Cardiolipins; C502521:Dis3 protein, Drosophila; D029721:Drosophila Proteins; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D020033:Protein Isoforms; D011506:Proteins; D014157:Transcription Factors; C483858:phosphatidylethanolamine; D008243:1-Acylglycerophosphocholine O-Acyltransferase; C514176:tafazzin protein, Drosophila