Disease relevance of TAZ

• Barth syndrome (BTHS) is an X-linked recessive disorder caused by mutations in the TAZ gene and is characterized by cardiomyopathy, short stature, neutropenia, and 3-methylglutaconic aciduria [1].
• Other findings associated with BTHS (skeletal myopathy, neutropenia, growth retardation, elevated urinary organic acids, and mitochondrial abnormalities) were either absent or inconsistent [2].
• X-linked cardiomyopathies with clinical manifestations similar to BTHS have been reported, and it has been proposed that they may be allelic [3].
• The X-linked gene G4.5 is responsible for different infantile dilated cardiomyopathies [3].
• The molecular studies have linked together what were formerly considered different conditions and have shown that the G4.5 gene is responsible for BTHS (OMIM 302060), X-linked endocardial fibroelastosis (OMIM 305300), and severe X-linked cardiomyopathy (OMIM 300069) [3].

High impact information on TAZ

• Different mRNAs can be produced by alternative splicing of the primary G4.5 transcript, encoding novel proteins that differ at the N terminus and in the central region [4].
• We now report the identification of unique mutations in one of the genes in this region, termed G4.5, expressed at high level in cardiac and skeletal muscle [4].
• A novel X-linked gene, G4.5. is responsible for Barth syndrome [4].
• Two genes have been identified for the X-linked forms (dystrophin and tafazzin), whereas three other genes (actin, lamin A/C, and desmin) cause autosomal dominant DCM; seven other loci for autosomal dominant DCM have been mapped but the genes have not been identified [5].
• Truncation mutants of TBX5 identified in patients with Holt-Oram syndrome were markedly impaired in their ability to associate with and be stimulated by TAZ [6].

Chemical compound and disease context of TAZ

• CONCLUSIONS: Abnormal cardiolipin is a specific diagnostic marker of cardiomyopathies caused by TAZ mutations [7].
• Body weight gain and feed conversion at 16 wks of age were improved (P less than 0.01) with TA and TAZ [8].

Biological context of TAZ

• Novel missense mutation (R94S) in the TAZ ( G4.5) gene in a Japanese patient with Barth syndrome [9].
• Sequence homology of the TAZ gene to a highly conserved superclass of acyltransferases (Neuwald's hypothesis) predicts a glycerophospholipid as the missing end product [10].
• Molecular analysis of the TAZ (G4.5) gene showed the c.877G > A mutation leading to the G197R amino acid substitution in patient 1, and the new splice donor c.829 + 1G > A genetic lesion in patient 2 [11].
• A linkage study of the X chromosome localized INVM to the Xq28 region near the BTHS locus, suggesting that these disorders are allelic [2].
• We screened the G4.5 gene for mutations in this family with SSCP and direct sequencing and found a novel glycine-to-arginine substitution at position 197 [2].

Anatomical context of TAZ

• The TAZ gene encodes Tafazzin, a putative phospholipid acyltranferase that is involved in the remodeling of cardiolipin, a phospholipid unique to the inner mitochondrial membrane [12].
• RT-PCR and transcription-coupled in vitro translation analysis were undertaken to determine the expression of alternatively spliced TAZ mRNA in mouse tissues and human cell lines [13].
• Only two tafazzin transcripts, both lacking exon 5, were expressed in murine tissues, whereas four tafazzin transcripts, all lacking exon 5, were observed in human umbilical vein vascular endothelial cells and U937 human monoblasts indicating a species-specific difference in the expression of TAZ mRNAs in mouse and humans [13].
• Our results showed a clear decrease of CL in combination with a marked increase of MLCL in fibroblasts from BTHS patients when compared with controls [14].
• Differentiation of U937 human monoblasts into macrophages did not alter expression of the tafazzin transcripts indicating that TAZ expression is independent of monocyte differentiation [13].

Associations of TAZ with chemical compounds

• Only one splice variant of the human TAZ gene encodes a functional protein with a role in cardiolipin metabolism [1].
• Here, we investigated the effects of Tafazzin, and hence cardiolipin deficiency in lymphoblasts from patients with Barth Syndrome, using blue-native polyacrylamide gel electrophoresis [12].
• At G4.5, DHEA did not induce formation of DNA ladder until it reached 200 microM [15].
• DHEA inhibited cell growth by causing cell cycle arrest primarily in the G0--G1 phase, and the effect was more pronounced at zero glucose (no glucose added, G0) than high glucose (4.5 mg/ml of the medium, G4.5) [15].
• TA and zeranol (Z) were tested singly and in combination (TAZ) [8].

Physical interactions of TAZ

• The transcriptional co-activator TAZ interacts differentially with transcriptional enhancer factor-1 (TEF-1) family members [16].

Other interactions of TAZ

• This finding provides further structure-function information about the G4.5 gene product and has implications for unexplained cases of severe infantile hypertrophic cardiomyopathy in males [2].
• We sequenced G4.5 in two kindreds with X-linked DCM and in two unrelated men, one with idiopathic DCM and the other with DCM of arrhythmogenic right ventricular dysplasia [17].
• Recent work extends the list of neutropenia genes to include WASp, Gfi-1, adaptin, and tafazzin [18].

Analytical, diagnostic and therapeutic context of TAZ

• 5. In this paper we report the sequence analysis of 11 additional familial cases: 8 were diagnosed as possibly affected with BTHS, and 3 were affected with X-linked dilated cardiomyopathies [3].
• Measurement of decreased CL levels in skin fibroblasts has previously been proposed as a diagnostic test for BTHS [14].
• METHODS: Prenatal diagnosis revealed that a male fetus was positive for a known familial arg94his TAZ gene mutation [19].
• We therefore analyzed X chromosome inactivation in 16 obligate carriers of BTHS, from six families, using PCR in the androgen-receptor locus [20].
• BTHS patients had a specific decrease of tetralinoleyl-CL concentrations in platelets (0.1-0.5 nmol/mg of protein; n = 4) compared with all control groups (2.3-5.5 nmol/mg of protein; n = 26) [21].

References