title: General mitochondrial trifunctional protein (TFP) deficiency as a result of either alpha- or beta-subunit mutations exhibits similar phenotypes because mutations in either subunit alter TFP complex expression and subunit turnover.
abstract: The mitochondrial trifunctional protein (TFP) is a multienzyme complex of the beta-oxidation cycle. Human TFP is an octamer composed of four alpha-subunits harboring long-chain enoyl-CoA hydratase and long-chain L-3-hydroxyacyl-CoA dehydrogenase and four beta-subunits encoding long-chain 3-ketoacyl-CoA thiolase. Mutations in either subunit may result in general TFP deficiency with reduced activity of all three enzymes. We report five new patients with alpha-subunit mutations and compare general TFP deficiency caused by alpha-subunit mutations (n = 15) to that caused by beta-subunit mutations (n = 13) with regard to clinical features, enzyme activity, mutations, thiolase expression, and thiolase protein turnover. Among patients with alpha-subunit mutations, the same three heterogeneous phenotypes reported in patients with beta-subunit mutations were observed: a lethal form with predominating cardiomyopathy; an infancy-onset, hepatic presentation; and a milder, later-onset, neuromyopathic form. Maternal HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) occurred with an incidence of 15 to 20%, as in families with beta-subunit mutations. Enzyme assays in fibroblasts revealed an identical biochemical pattern in both groups. alpha-Subunit mutational analysis demonstrated molecular heterogeneity, with 53% (9 of 17) truncating mutations. In contrast, patients with beta-subunit mutations had predominantly missense mutations. Thiolase expression in fibroblasts was as markedly reduced in alpha-subunit patients as in the beta-subunit group with similarly increased thiolase degradation, presumably secondary to TFP complex instability. TFP deficiency as a result of either alpha- or beta-subunit mutations presents with similar, heterogeneous phenotypes. Both alpha- and beta-subunit mutations result in TFP complex instability, demonstrating that the mechanism of disease is the same in alpha- or beta-mutation-derived disease and explaining the biochemical and clinical similarities.
authors: Department of Pediatrics and Vanderbilt Children's Hospital, Nashville, TN 37232, USA. ute.spiekerkoetter@uni-duesseldorf.de
authors: Ute
authors: U
authors: Spiekerkoetter
authors: Zaza
authors: Z
authors: Khuchua
authors: Zou
authors: Z
authors: Yue
authors: Michael J
authors: MJ
authors: Bennett
authors: Arnold W
authors: AW
authors: Strauss
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism; D000102:Acetyl-CoA C-Acyltransferase / Q000378:metabolism; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002460:Cell Line; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008107:Liver Diseases / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase; D063991:Mitochondrial Trifunctional Protein; D009097:Multienzyme Complexes / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D010641:Phenotype
chemical_list: D009097:Multienzyme Complexes; D015094:3-Hydroxyacyl CoA Dehydrogenases; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase; D000102:Acetyl-CoA C-Acyltransferase; D063991:Mitochondrial Trifunctional Protein