title: Lipoamide dehydrogenase deficiency due to a novel mutation in the interface domain.
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.
authors.affiliation: Neonatology and Pediatric Departments, Soroka Medical Center, Beer-Sheva, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Shany
authors.forename: A
authors.initials: A
authors.lastname: Saada
authors.forename: D
authors.initials: D
authors.lastname: Landau
authors.forename: A
authors.initials: A
authors.lastname: Shaag
authors.forename: E
authors.initials: E
authors.lastname: Hershkovitz
authors.forename: O N
authors.initials: ON
authors.lastname: Elpeleg
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D008058:Dihydrolipoamide Dehydrogenase / Q000737:chemistry* / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D004792:Enzyme Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007655:Ketoglutarate Dehydrogenase Complex / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000201:enzymology; D008297:Male; D008931:Mitochondria, Muscle / Q000201:enzymology; D008969:Molecular Sequence Data; D009132:Muscles / Q000201:enzymology / Q000473:pathology; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D017433:Protein Structure, Secondary; D011768:Pyruvate Dehydrogenase Complex / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology
chemical_list: D004792:Enzyme Precursors; D011768:Pyruvate Dehydrogenase Complex; D007655:Ketoglutarate Dehydrogenase Complex; D008058:Dihydrolipoamide Dehydrogenase