title: A novel mutation in the dihydrolipoamide dehydrogenase E3 subunit gene (DLD) resulting in an atypical form of alpha-ketoglutarate dehydrogenase deficiency.
abstract: The alpha-ketoglutarate dehydrogenase complex (KGDC) catalyses the decarboxylation of alpha-ketoglutarate into succinyl-coenzyme A in the Krebs cycle. This enzymatic complex is made up of three subunits (E1, encoded by PDHA1; E2, encoded by DLST; and E3, encoded by DLD). The E3 subunit is common to two other enzymatic complexes, namely pyruvate dehydrogenase complex (PDC) and branched-chain ketoacid dehydrogenase complex (BCKDC). KGDC deficiency is a rare autosomal recessive disorder, most often presenting with severe encephalopathy and hyperlactatemia with neonatal onset. We found a KGDC deficiency in cultured skin fibroblasts from three siblings born to consanguinous parents. E3 subunit activity was shown to be deficient (20% of control values), despite the absence of usual clinical clues to E3 deficiency, i.e. accumulation of pyruvate and branched-chain amino acids in plasma and branched-chain alpha-ketoacids in urine. RT-PCR of E3 mRNA from the three patients, followed by sequencing, revealed an homozygous c.1444A>G substitution located in E3 exon 13, predictive of a p.R482G (or R447G in the processed gene product) substitution in a highly conserved domain of the protein. Only eleven E3 mutations have been reported so far. The only other case of E3 deficiency without clinical or biochemical evidences of PDC and BCKDC deficiencies has been ascribed to a c.1436A>T (p.D479V; or D444V in the processed gene product) mutation, very close to the mutation reported herein. Since c.1444A>G (p.R482G; or R447G in the processed gene product) and c.1436A>T (p.D479V; or D444V in the processed gene product) lie within the interface domain of E3 with E2 (KGDC and BCKDC) or the E3-binding protein (PDC), our data suggest that interaction of E3 with these other subunits differs in some extent among KGDC, PDC, and BCKDC.
authors.affiliation: Unité Inserm U393, Hôpital Necker Enfants-Malades, Paris, France.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Odièvre
authors.forename: Dominique
authors.initials: D
authors.lastname: Chretien
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Brian H
authors.initials: BH
authors.lastname: Robinson
authors.forename: Renée
authors.initials: R
authors.lastname: Dumoulin
authors.forename: Sahben
authors.initials: S
authors.lastname: Masmoudi
authors.forename: Noman
authors.initials: N
authors.lastname: Kadhom
authors.forename: Agnès
authors.initials: A
authors.lastname: Rötig
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Bonnefont
mesh_terms: D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000172:deficiency / Q000235:genetics; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001264:Athetosis / Q000235:genetics; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics; D002819:Chorea / Q000235:genetics; D003241:Consanguinity; D008058:Dihydrolipoamide Dehydrogenase / Q000737:chemistry / Q000235:genetics*; D005091:Exons / Q000235:genetics; D017809:Fatal Outcome; D005347:Fibroblasts / Q000201:enzymology; D005808:Genes, Recessive; D006801:Humans; D007231:Infant, Newborn; D007655:Ketoglutarate Dehydrogenase Complex / Q000172:deficiency* / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009123:Muscle Hypotonia / Q000235:genetics; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary / Q000235:genetics; D021122:Protein Subunits; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity
chemical_list: D021122:Protein Subunits; D011768:Pyruvate Dehydrogenase Complex; D007655:Ketoglutarate Dehydrogenase Complex; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide); D008058:Dihydrolipoamide Dehydrogenase