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Leucine-sensitive hyperinsulinaemic hypoglycaemia in patients with loss of function mutations in 3-Hydroxyacyl-CoA

Amanda J Heslegrave1, Ritika R Kapoor, Simon Eaton

  • 1The Institute of Child Health, University College London, London, WC1N 1EH, UK.

Orphanet Journal of Rare Diseases
|May 16, 2012
PubMed

Insights

Loss of function mutations in 3-Hydroxyacyl-CoA Dehydrogenase (HADH) cause protein-sensitive hyperinsulinaemic hypoglycaemia (HH). This study reveals that the interaction between HADH and glutamate dehydrogenase (GDH) is lost in patients, explaining leucine-induced HH.

Area of Science:

  • Biochemistry
  • Genetics
  • Metabolic Disorders

Background:

  • Loss-of-function mutations in 3-Hydroxyacyl-CoA Dehydrogenase (HADH) lead to protein-sensitive hyperinsulinaemic hypoglycaemia (HH).
  • HADH is crucial for mitochondrial fatty acid beta-oxidation.
  • Mutations in GLUD1 also cause protein-sensitive HH, suggesting a link with glutamate dehydrogenase (GDH).

Purpose of the Study:

  • To investigate the mechanism behind protein sensitivity in patients with HADH mutations.
  • To explore the potential protein-protein interaction between HADH and GDH.

Main Methods:

  • Oral leucine tolerance tests were performed on patients with HADH mutations and controls.
  • Glutamate dehydrogenase (GDH) activity and guanosine triphosphate (GTP) inhibition were assessed in lymphoblast homogenates.
  • Immunoprecipitation assays were used to examine HADH-GDH protein interactions.

Main Results:

  • Patients with HADH mutations exhibited severe hyperinsulinaemic hypoglycaemia upon leucine challenge, unlike controls.
  • Basal GDH activity and GTP inhibition were comparable between patients and controls.
  • HADH protein co-immunoprecipitation with GDH was observed in controls but absent in patients.

Conclusions:

  • A direct protein-protein interaction exists between GDH and HADH.
  • This interaction is disrupted in patients with HADH mutations, causing leucine-induced hyperinsulinaemic hypoglycaemia.
  • The observed effect is distinct from the GTP-related mechanism seen in GLUD1 mutations.
Abstract

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