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Role of short-chain hydroxyacyl CoA dehydrogenases in SCHAD deficiency

2007; Elsevier BV; Volume: 368; Issue: 1 Linguagem: Inglês

10.1016/j.bbrc.2007.10.188

1090-2104

Charlotta Filling, Brigitte Keller, Daniel Hirschberg, Hanns‐Ulrich Marschall, Hans Jörnvall, Michael J. Bennett, Udo Oppermann,

Erythrocyte Function and Pathophysiology

Short-chain hydroxyacyl CoA dehydrogenase deficiency is an ill-defined, severe pediatric disorder of mitochondrial fatty acid β-oxidation of short-chain hydroxyacyl CoAs. To understand the relative contributions of the two known short-chain hydroxyacyl CoA dehydrogenases (HADH) tissue biopsies of six distinct family individuals were analyzed and kinetic parameters were compared. Steady-state kinetic constants for HADH 1 and HADH 2 suggest that type 1 is the major enzyme involved in mitochondrial β-oxidation of short-chain hydroxyacyl-CoAs. Two patients are heterozygous carriers of a HADH 1 polymorphism, whereas no mutation is detected in the HADH 2 gene of all patients. The data suggest that protein interactions rather than HADH mutations are responsible for the disease phenotype. Pull-down experiments of recombinant HADH 1 and 2 with human mitochondrial extracts reveal two proteins interacting with HADH 1, one of which was identified as glutamate dehydrogenase. This association provides a possible link between fatty acid metabolism and the hyperinsulinism/hyperammonia syndrome.