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

Abstract

SUMMARY: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. (Lab Invest 2002, 82:335-344).

A Role for Peroxisome Proliferator-activated Receptor γ Coactivator 1 (PGC-1) in the Regulation of Cardiac Mitochondrial Phospholipid Biosynthesis

“…Ϫ/Ϫ Hearts-Mitochondrial cristae "stacking" abnormalities similar to those observed in the adult PGC-1␣␤ Ϫ/Ϫ hearts have been described previously in the heart and skeletal muscle of Barth syndrome patients (2). Barth syndrome is a genetic disorder caused by mutations in …”

“…In addition, the mitochondrial membrane includes a class of specialized phospholipid, cardiolipin (CL) (1). The importance of PL for mitochondrial integrity and function is underscored by the phenotype of Barth syndrome, which can be caused by a genetic defect in CL remodeling resulting in alterations in mitochondrial ultrastructure and respiratory function causing cardiac and skeletal myopathies (2).…”

“…The integrity and function of cellular organelles depend, in part, on their membrane structure, including the phospholipid (PL) 2 component. This is particularly true for the mitochondrion, which is supported by a complex membranous structure that comprises the cristae, a labyrinth system that increases surface area allowing for the electron transport complex that supports capacity ATP production.…”

Left Ventricular Noncompaction

“…47,48 The products of this gene, known as tafazzins, are expressed primarily in heart and muscle cells, and are proposed to have acyltransferase functions within mitochondria. 49 TAZ mutations have been identified repeatedly in some of the larger series of LVNC, but account for a small proportion of cases. 12,[14][15][16] …”

Translational Research in Pediatrics IV: Solid Tissue Collection and Processing

“…233 The AFS has the practical limitation of its inability to assess each anatomic region separately, resulting in the development of an agonal stress rating system that evaluates the degree of stress based on gene expression data. 237 The agonal stress rating can reduce the number of false-positive findings by allowing a quantitative 113 • PPT1, caspase-3, cleaved-PARP, caspase-9, ROS, and SOD-2 113 • Infi ltrative glioma and gliosis 53 • EGFR 53 • Autism [197][198][199] • Neuronal microexons, 197 • Infantile X-linked dilated cardiomyopathy 200 • Saturated fatty acids, mitochondria structure 200 • Dilated cardiomyopathy and congenital heart disease 137…”