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: 3.68). 04/2002; 82(3):335-44. DOI: 10.1038/labinvest.3780427
Source: PubMed


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.

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Available from: Michael A Ralston, Mar 31, 2014
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    • "The fact that there is no apparent correlation between genotype and phenotype (Johnston et al. 1997) indicates that there are additional modifying factors and (or) compensating mechanisms. TAZ belongs to the family of acyltransferases that are involved in glycerolipid biosynthesis and remodeling (Neuwald 1997; Bissler et al. 2002), although the activity of tafazzin itself has not been directly identified. Fatty acid radioabeling experiments using cultured skin fibroblasts from Barth syndrome patients have identified a potential defective remodeling of cardiolipin and phophatidylglycerol, which has been correlated with a reduction in cardiolipin levels (Vreken et al. 2000). "
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