A mutation in the E1 alpha subunit of pyruvate dehydrogenase associated with variable expression of pyruvate dehydrogenase complex deficiency.

Defects in pyruvate dehydrogenase, the first catalytic component of the pyruvate dehydrogenase complex, are the most common cause of pyruvate dehydrogenase complex deficiency. A family with variable pyruvate dehydrogenase complex deficiency had been described in which cultured skin fibroblasts of affected family members had normal pyruvate dehydrogenase complex activity, but different tissues and blood lymphocytes had significantly diminished activities. Enzymatic activity and immunoblot studies indicated that pyruvate dehydrogenase was affected. Further evidence is presented here showing that the defect affecting pyruvate dehydrogenase complex activity is posttranscriptional. Sequencing of the coding region of the alpha-subunit of pyruvate dehydrogenase revealed a point mutation in the codon for amino acid 234 resulting in a substitution of glycine for arginine. Study of other members of the family suggested that this mutation is inherited in a sex-linked mode. The point mutation is located in a highly conserved region of the pyruvate dehydrogenase alpha-subunit gene that contains both hydrophobic and positively charged amino acid residues. Variable expression of pyruvate dehydrogenase complex deficiency in this case may be due to instability of the pyruvate dehydrogenase heterotetramer in specific tissues because of a disruption in subunit-subunit interaction.