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Glutamine Flux Imaging Using Genetically Encoded Sensors
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Glutamine Flux Imaging Using Genetically Encoded Sensors

Published on: July 31, 2014

Molecular characterisation of glutamate dehydrogenase gene defects in Japanese patients with congenital

H Fujioka1, Y Okano, H Inada

  • 1Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan.

European Journal of Human Genetics : EJHG
|February 13, 2002
PubMed

Insights

Congenital hyperinsulinism and hyperammonaemia (CHH) results from glutamate dehydrogenase (GDH) gene mutations. Specific mutations L413V and G446D cause varying enzyme dysfunction, correlating with CHH patient phenotypes.

Area of Science:

  • Biochemistry
  • Genetics
  • Pediatrics

Background:

  • Congenital hyperinsulinism and hyperammonaemia (CHH) is a metabolic disorder linked to glutamate dehydrogenase (GDH) dysregulation.
  • GDH enzyme activity is modulated by GTP and ADP, crucial for regulating ammonia and glucose metabolism.

Purpose of the Study:

  • To characterize GDH gene mutations in two Japanese patients with CHH.
  • To correlate specific GDH mutations with biochemical and clinical phenotypes.

Main Methods:

  • Genetic analysis of the GDH gene in patients and their families.
  • Measurement of GDH enzyme activity and allosteric regulation in lymphoblasts.
  • COS cell expression studies to confirm pathogenicity of identified mutations.

Main Results:

  • Identified heterozygous, de novo GDH mutations L413V in patient 1 and G446D in patient 2.
  • Patient 1 (L413V) exhibited mild insensitivity to GTP inhibition and higher basal GDH activity, correlating with milder symptoms.
  • Patient 2 (G446D) showed severe GTP insensitivity, with mutations located in critical functional sites of the GDH enzyme.

Conclusions:

  • The identified GDH mutations L413V and G446D are disease-causing in CHH.
  • Mutation location and biochemical effects explain the varying clinical severity observed in the patients.
  • The antenna-like structure of GDH is critical for enzyme activity and is impacted by these mutations.

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