This report describes Barth syndrome, which is a subtype of 3-methylglutaconic aciduria; Barth syndrome is inherited in an X-linked recessive pattern. The human gene implicated in this disease is TAZ, which encodes tafazzin, an inner mitochondrial membrane protein necessary for cardiolipin remodeling. There is a single fly ortholog, Taz, for which insertion alleles, insertion excision alleles, and RNAi-targeting constructs have been generated.
The human transgene Hsap\TAFAZZIN has been expressed in flies but has not been analyzed in the context of Barth syndrome. Heterologous rescue (functional complementation) has been demonstrated.
Deletion alleles of the fly Taz gene that remove the first coding exon and thus the full-length isoform of taffazin (one of four isoforms) are viable; homozygotes display low cardiolipin levels, changes in cardiolipin fatty acyl composition, motor weakness, and abnormal mitochondria, all characteristic of Barth syndrome; male sterility is also observed.
Genetic interaction studies using Dmel\Taz have shown that the male sterility phenotype is suppressed in mutants of iPLA2-VIA, another enzyme that effects cardiolipin levels; concomitant characterization of cardiolipins in single and double mutants implicates the composition and levels of cardiolipins in the pathogenesis of Barth syndrome.
[updated Jul. 2017 by FlyBase; FBrf0222196]
Methylglutaconic aciduria is a clinically and genetically heterogeneous disorder whose metabolic landmark is urinary excretion of 3-methylglutaconic acid (3-MGA).
[BARTH SYNDROME; BTHS](https://omim.org/entry/302060)
[TAFAZZIN, PHOSPHOLIPID-LYSOPHOSPHOLIPID TRANSACYLASE; TAFAZZIN](https://omim.org/entry/300394)
Symptoms of Barth syndrome often include combinations in varying degrees of cardiomyopathy, neutropenia, hypotonia, muscle weakness, delayed growth, lack of stamina, varying degrees of physical disability, distinctive facial features (most evident in infancy), and methylglutaconic aciduria. The age at which individuals with Barth syndrome display symptoms or are diagnosed varies greatly. The severity of signs and symptoms among affected individuals is also highly variable. [from Gene Reviews, http://www.ncbi.nlm.nih.gov/books/NBK247162 2016.1.27]
Barth syndrome is characterized by dilated cardiomyopathy, neutropenia, skeletal myopathy, and abnormal mitochondria. Cardiomyopathy and neutropenia are the main causes of high mortality, predominantly in the first 5 years of life, however some patients reach adulthood. Increased excretion of 3-methylglutaconic acid is a characteristic biochemical marker of the disease but is not always present. [from MIM:302060, 2016.1.16]
Barth syndrome occurs almost exclusively in males; female carriers are unaffected.
Barth syndrome exhibits an X-linked recessive pattern of transmission. It has been shown to be caused by mutations in the TAZ gene (also referred to as the G4.5 gene), which encodes tafazzin. [from MIM:302060, 2016.1.16]
Abnormal mitochondria have been observed in muscle fibers. [from Gene Reviews, http://www.ncbi.nlm.nih.gov/books/NBK247162 2016.1.27]
tafazzin is a transacylase located on the inner mitochondrial membrane which catalyzes the remodeling of the acyl chains of immature cardiolipin to a mature, predominantly tetralinoleylcardiolipin. Barth syndrome patients have a reduced content and an altered composition of cardiolipin. [from Gene Reviews, http://www.ncbi.nlm.nih.gov/books/NBK247162 2016.1.27]
A link between mitochondrial dysfunction and the production of reactive oxygen species (ROS) has been postulated (Saric et. al., 2016; pubmed:26834781).
[updated Mar. 2016 by FlyBase; FBrf0222196]
Patients with Barth syndrome have decreased cardiolipin, a component of the inner mitochondrial membrane necessary for proper functioning of the electron transport chain. Tafazzin protein is necessary for acyl-specific remodeling of cardiolipin, which promotes structural uniformity and molecular symmetry among the cardiolipin molecular species; inhibition of this pathway leads to changes in mitochondrial architecture and function. [from MIM:302060, 2016.1.16]
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human TAFAZZIN (1 Drosophila to 1 human). Dmel\Taz shares 42% identity and 56% similarity with the human gene.
