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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.

journal_name

Pediatr Res

journal_title

Pediatric research

authors

Spiekerkoetter U,Khuchua Z,Yue Z,Bennett MJ,Strauss AW

doi

10.1203/01.PDR.0000103931.80055.06

subject

Has Abstract

pub_date

2004-02-01 00:00:00

pages

190-6

issue

eissn

0031-3998

issn

1530-0447

pii

01.PDR.0000103931.80055.06

journal_volume

pub_type

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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.