Lipoamide dehydrogenase deficiency due to a novel mutation in the interface domain

Biochem Biophys Res Commun. 1999 Aug 19;262(1):163-6. doi: 10.1006/bbrc.1999.1133.

Abstract

An infant with a neurodegenerative disorder accompanied by lactic acidemia is described. In muscle homogenate, the activity of lipoamide dehydrogenase (LAD), the third catalytic subunit of pyruvate dehydrogenase complex (PDHc), alpha-ketoglutarate dehydrogenase complex (KGDHc), and branched-chain keto acid dehydrogenase complex was reduced to 15% of the control. The activity of PDHc was undetectable and the activity of KGDHc was 2% of the control mean. The immunoreactive LAD protein was reduced to about 10% of the control. Direct sequencing of LAD cDNA revealed only one mutation, substituting Asp for Val at position 479 of the precursor form. The mutation resides within the interface domain and likely perturbs stable dimerization. The phenotypic heterogeneity in LAD deficiency is not directly correlated with the residual LAD activity but rather with its impact on the multienzymatic complex activity.

Publication types

  • Case Reports

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Dihydrolipoamide Dehydrogenase / chemistry*
  • Dihydrolipoamide Dehydrogenase / deficiency*
  • Dihydrolipoamide Dehydrogenase / genetics
  • Dihydrolipoamide Dehydrogenase / metabolism
  • Dimerization
  • Enzyme Precursors / chemistry
  • Enzyme Precursors / genetics
  • Enzyme Precursors / metabolism
  • Female
  • Heterozygote
  • Humans
  • Infant
  • Ketoglutarate Dehydrogenase Complex / chemistry
  • Ketoglutarate Dehydrogenase Complex / deficiency
  • Ketoglutarate Dehydrogenase Complex / genetics
  • Ketoglutarate Dehydrogenase Complex / metabolism
  • Lymphocytes / enzymology
  • Male
  • Mitochondria, Muscle / enzymology
  • Molecular Sequence Data
  • Muscles / enzymology
  • Muscles / pathology
  • Mutation*
  • Neurodegenerative Diseases / enzymology
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / pathology
  • Phenotype
  • Protein Structure, Secondary
  • Pyruvate Dehydrogenase Complex / chemistry
  • Pyruvate Dehydrogenase Complex / genetics
  • Pyruvate Dehydrogenase Complex / metabolism
  • Pyruvate Dehydrogenase Complex Deficiency Disease / enzymology
  • Pyruvate Dehydrogenase Complex Deficiency Disease / genetics
  • Pyruvate Dehydrogenase Complex Deficiency Disease / pathology

Substances

  • Enzyme Precursors
  • Pyruvate Dehydrogenase Complex
  • Ketoglutarate Dehydrogenase Complex
  • Dihydrolipoamide Dehydrogenase