Barth syndrome (BTHS), a rare, X-linked, recessive disease, is characterized by 
neutropenia and cardiomyopathy. BTHS is caused by loss-of-function mutations of 
the tafazzin (TAZ) gene. We developed a model of BTHS by transfecting human HL60 
myeloid progenitor cells with TAZ-specific shRNAs. Results demonstrate a 
significant downregulation in TAZ expression, mimicking the effects of naturally 
occurring truncation mutations in TAZ. Flow cytometry analyses of cells with 
TAZ-specific, but not scrambled, shRNAs demonstrate nearly twofold increase in 
the proportion of annexin V-positive cells and significantly increased 
dissipation of mitochondrial membrane potential as determined by DIOC6 staining. 
Transfection of TAZ-specific shRNA had similar effects in U937 myeloid cells but 
not in lymphoid cell lines. Further studies in HL60 myeloid progenitor cells 
revealed aberrant release of cytochrome c from mitochondria and significantly 
elevated levels of activated caspase-3 in response to TAZ knockdown. Treatment 
with caspase-specific inhibitor zVAD-fmk resulted in substantially reduced 
apoptosis to near-normal levels. These data suggest that neutropenia in BTHS is 
attributable to increased dissipation of mitochondrial membrane potential, 
aberrant release of cytochrome c, activation of caspase-3, and accelerated 
apoptosis of myeloid progenitor cells, and that this defect can be partially 
restored in vitro by treatment with caspase-specific inhibitors.