Barth syndrome is an X-linked disorder caused by mutations in the TAZ gene whose protein products, tafazzins, are phospholipid transacylases. The phospholipid most affected by the disease is cardiolipin, a dimeric phospholipid localized exclusively in mitochondria and required for optimal mitochondrial function. Defective cardiolipin metabolism appears to be a major contributing factor underlying the Barth syndrome, which is generally characterized by cardioskeletal myopathy with neutropenia and abnormal mitochondria. Although the cardinal characteristics of Barth syndrome have been clearly defined, the severity of these symptoms are often quite variable, even among patients with identical TAZ mutations, suggesting the existence of additional genetic factors that modify the disease expression. The proposed research utilizes a Drosophila model of Barth syndrome to identify the genetic modifiers of Barth syndrome in genome-wide suppressor screens. Specifically, the role of two identified suppressors will be characterized, one encodes a Hsp40 co-chaperone, the other a phospholipase. By uncovering genetic modifiers of Barth syndrome, we will not only gain new insight into the pathogenetic mechanism of the disease, but also identify potential targets for therapeutic intervention.
Project Narrative Barth syndrome, a genetic disorder caused by mutations in the TAZ gene, is characterized by cardioskeletal myopathy with neutropenia and abnormal mitochondria. However, the severity of these symptoms are often quite variable, even among patients with identical TAZ mutations, suggesting the existence of additional factors that modify the disease expression. Uncovering these modifiers will not only shed light on the pathogenic mechanism of the disease, but also provide potential targets for therapeutic intervention, which is the long-term goal of the proposed research.
| Schlame, Michael; Acehan, Devrim; Berno, Bob et al. (2012) The physical state of lipid substrates provides transacylation specificity for tafazzin. Nat Chem Biol 8:862-9 |
