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Hum Mol Genet. 2016 May 1;25(9):1754-70. doi: 10.1093/hmg/ddw046. Epub 2016 Feb 16.

Defining functional classes of Barth syndrome mutation in humans.

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Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2185, USA.
Cancer Research UK, The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK.
Department of Chemistry and Biochemistry, Molecular Biology Institute, and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095-1569, USA.
Division of Biology and Biomedical Sciences, Graduate School of Arts and Sciences, Washington University, St. Louis, MO 63130-4899, USA.
Departments of Clinical Chemistry and Pediatrics, Laboratory Genetic Metabolic Diseases and.
Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, The Netherlands and.
Integrated Imaging Center, Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2185, USA,


The X-linked disease Barth syndrome (BTHS) is caused by mutations in TAZ; TAZ is the main determinant of the final acyl chain composition of the mitochondrial-specific phospholipid, cardiolipin. To date, a detailed characterization of endogenous TAZ has only been performed in yeast. Further, why a given BTHS-associated missense mutation impairs TAZ function has only been determined in a yeast model of this human disease. Presently, the detailed characterization of yeast tafazzin harboring individual BTHS mutations at evolutionarily conserved residues has identified seven distinct loss-of-function mechanisms caused by patient-associated missense alleles. However, whether the biochemical consequences associated with individual mutations also occur in the context of human TAZ in a validated mammalian model has not been demonstrated. Here, utilizing newly established monoclonal antibodies capable of detecting endogenous TAZ, we demonstrate that mammalian TAZ, like its yeast counterpart, is localized to the mitochondrion where it adopts an extremely protease-resistant fold, associates non-integrally with intermembrane space-facing membranes and assembles in a range of complexes. Even though multiple isoforms are expressed at the mRNA level, only a single polypeptide that co-migrates with the human isoform lacking exon 5 is expressed in human skin fibroblasts, HEK293 cells, and murine heart and liver mitochondria. Finally, using a new genome-edited mammalian BTHS cell culture model, we demonstrate that the loss-of-function mechanisms for two BTHS alleles that represent two of the seven functional classes of BTHS mutation as originally defined in yeast, are the same when modeled in human TAZ.

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