Article

Infantile Dilated X-Linked Cardiomyopathy, G4.5 Mutations, Altered Lipids, and Ultrastructural Malformations of Mitochondria in Heart, Liver, and Skeletal Muscle

Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
Laboratory Investigation (Impact Factor: 3.83). 04/2002; 82(3):335-44. DOI: 10.1038/labinvest.3780427
Source: PubMed

ABSTRACT Mutations in the Xq28 gene G4.5 lead to dilated cardiomyopathy (DCM). Differential splicing of G4.5 results in a family of proteins called "tafazzins" with homology to acyltransferases. These enzymes assemble fatty acids into membrane lipids. 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. We examined the ultrastructure of heart, liver, and muscle biopsy specimens in these three DCM types; we used gas chromatography to compare fatty acid composition in heart, liver, and muscle autopsy specimens of two patients of kindred 1 with that of controls. In X-linked DCM, G4.5 had a stop codon (E188X), a nonsense mutation, in kindred 1 and an amino acid substitution (G240R), a missense mutation, in kindred 2. In the two men with isolated DCM, G4.5 was not mutated. Ultrastructural mitochondrial malformations were present in the biopsy tissues of the patients with DCM. Cardiac biopsy specimens of both kindreds with X-linked DCM exhibited greatly enlarged mitochondria with large bundles of stacked, compacted, disarrayed cristae that differed from those of the two types of isolated DCM. Autopsy tissue of patients with X-linked DCM had decreased unsaturated and increased saturated fatty acid concentrations. Seven of 13 published G4.5 missense mutations, including the one presented here, occur in acyltransferase motifs. Impaired acyltransferase function could result in increased fatty acid saturation that would decrease membrane fluidity. Mitochondrial membrane proliferation may be an attempt to compensate for impaired function of acyltransferase. Cardiac ultrastructure separates X-linked DCM with G4.5 mutations from the two types of isolated DCM without G4.5 mutations. Electron microscopy of promptly fixed myocardial biopsy specimens has a role in defining the differential diagnosis of DCM. Mutational analysis of the G4.5 gene also serves this purpose.

Download full-text

Full-text

Available from: Michael A Ralston, Mar 31, 2014
0 Followers
 · 
121 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Tafazzins, a group of proteins that are defective in patients with Barth syndrome, are produced by alternate splicing of the gene G4.5 or TAZ. 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. 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. Only TAZ lacking exon 5 was expressed in murine heart. Differentiation of U937 human monoblasts into macrophages did not alter expression of the tafazzin transcripts indicating that TAZ expression is independent of monocyte differentiation. Cloning and in vitro expression of both murine and human tafazzin cDNA revealed two prominent protein bands that corresponded to the expected sizes of alternative translation. A novel fifth motif, identified as critical for the glycerolphosphate acyltransferase family, was observed in human tafazzin. The presence of a mutation in this region in Barth syndrome patients indicates that this motif is essential for tafazzin function.
    Biochemistry and Cell Biology 11/2004; 82(5):569-76. DOI:10.1139/o04-055 · 2.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The heart is highly dependent for its function on oxidative energy generated in mitochondria, primarily by fatty acid β-oxidation, respiratory electron chain and oxidative phosphorylation. Defects in mitochondrial structure and function have been found in association with cardiovascular diseases such as dilated and hypertrophy cardiomyopathy, cardiac conduction defects and sudden death, ischemic and alcoholic cardiomyopathy, as well as myocarditis. While a subset of these mitochondrial abnormalities have a defined genetic basis (e.g. mitochondrial DNA changes leading to oxidative phosphorylation dysfunction,fatty acid β-oxidation defects due to specific nuclear DNA mutations), other abnormalities appear to be due to a more sporadic or environmental cardiotoxic insult or have not yet been characterized. This review focuses on abnormalities in mitochondrial bioenergetic function and mitochondrial DNA defects associated with cardiovascular diseases, their significance in cardiac pathogenesis as well as on the available diagnostic and therapeutic options. A concise background concerning mitochondrial biogenesis and bioenergetic pathways during cardiac growth,development and aging will also be provided.
    Revista Espa de Cardiologia 01/2002; 55(12). DOI:10.1016/S0300-8932(02)76802-4 · 3.34 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The heart is highly dependent for its function on oxidative energy generated in mitochondria, primarily by fatty acid beta-oxidation, respiratory electron chain and oxidative phosphorylation. Defects in mitochondrial structure and function have been found in association with cardiovascular diseases such as dilated and hypertrophy cardiomyopathy, cardiac conduction defects and sudden death, ischemic and alcoholic cardiomyopathy, as well as myocarditis. While a subset of these mitochondrial abnormalities have a defined genetic basis (e.g. mitochondrial DNA changes leading to oxidative phosphorylation dysfunction,fatty acid beta-oxidation defects due to specific nuclear DNA mutations), other abnormalities appear to be due to a more sporadic or environmental cardiotoxic insult or have not yet been characterized.This review focuses on abnormalities in mitochondrial bioenergetic function and mitochondrial DNA defects associated with cardiovascular diseases, their significance in cardiac pathogenesis as well as on the available diagnostic and therapeutic options. A concise background concerning mitochondrial biogenesis and bioenergetic pathways during cardiac growth,development and aging will also be provided.
    Revista Espa de Cardiologia 01/2003; 55(12):1293-310. · 3.34 Impact Factor