The cellular and molecular mechanisms for neutropenia in Barth syndrome

Eur J Haematol. 2012 Mar;88(3):195-209. doi: 10.1111/j.1600-0609.2011.01725.x. Epub 2011 Dec 4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics
  • Barth Syndrome / complications*
  • Cardiolipins / metabolism
  • Cell Line, Tumor
  • Cell Survival / genetics
  • Gene Expression Regulation
  • Gene Silencing
  • HL-60 Cells
  • Humans
  • Jurkat Cells
  • Membrane Potential, Mitochondrial / genetics
  • Myeloid Progenitor Cells / metabolism
  • Neutropenia / etiology*
  • Neutropenia / metabolism*
  • Precursor Cells, T-Lymphoid / metabolism
  • RNA, Small Interfering
  • Transcription Factors / genetics
  • U937 Cells


  • Cardiolipins
  • RNA, Small Interfering
  • TAZ protein, human
  • Transcription Factors