Molecular characterization of 82 patients with pyruvate dehydrogenase complex deficiency. Structural implications of novel amino acid substitutions in E1 protein

Mol Genet Metab. 2011 Dec;104(4):507-16. doi: 10.1016/j.ymgme.2011.08.008. Epub 2011 Aug 18.


Background: Pyruvate dehydrogenase complex (PDHc) deficiencies are an important cause of primary lactic acidosis. Most cases result from mutations in the X-linked gene for the pyruvate dehydrogenase E1α subunit (PDHA1) while a few cases result from mutations in genes for E1β (PDHB), E2 (DLAT), E3 (DLD) and E3BP (PDHX) subunits or PDH-phosphatase (PDP1).

Aim: To report molecular characterization of 82 PDHc-deficient patients and analyze structural effects of novel missense mutations in PDHA1.

Methods: PDHA1 variations were investigated first, by exon sequencing using a long range PCR product, gene dosage assay and cDNA analysis. Mutation scanning in PDHX, PDHB, DLAT and DLD cDNAs was further performed in unsolved cases. Novel missense mutations in PDHA1 were located on the tridimensional model of human E1 protein to predict their possible functional consequences.

Results: PDHA1 mutations were found in 30 girls and 35 boys. Three large rearrangements, including two contiguous gene deletion syndrome were identified. Novel missense, frameshift and splicing mutations were also delineated and a nonsense mutation in a mosaic male. Mutations p.Glu75Ala, p.Arg88Ser, p.Arg119Trp, p.Gly144Asp, p.Pro217Arg, p.Arg235Gly, p.Tyr243Cys, p.Tyr243Ser, p.Arg245Gly, p.Pro250Leu, p.Gly278Arg, p.Met282Val, p.Gly298Glu in PDHA1 were predicted to impair active site channel conformation or subunit interactions. Six out of the seven patients with PDHB mutations displayed the recurrent p.Met101Val mutation; 9 patients harbored PDHX mutations and one patient DLD mutations.

Conclusion: We provide an efficient stepwise strategy for mutation screening in PDHc genes and expand the growing list of PDHA1 mutations analyzed at the structural level.

MeSH terms

  • Adolescent
  • Amino Acid Substitution*
  • Base Sequence
  • Catalytic Domain
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Female
  • Fibroblasts / enzymology
  • Fibroblasts / metabolism
  • Gene Dosage
  • Humans
  • Hydrogen Bonding
  • INDEL Mutation
  • Infant
  • Infant, Newborn
  • Male
  • Molecular Sequence Data
  • Pyruvate Dehydrogenase (Lipoamide) / genetics*
  • Pyruvate Dehydrogenase Complex / chemistry
  • Pyruvate Dehydrogenase Complex / genetics
  • Pyruvate Dehydrogenase Complex / metabolism
  • Pyruvate Dehydrogenase Complex Deficiency Disease / genetics*
  • Sequence Analysis, DNA


  • Pyruvate Dehydrogenase Complex
  • Pyruvate Dehydrogenase (Lipoamide)
  • pyruvate dehydrogenase E1alpha subunit