Mutation of E1α gene in a female patient with pyruvate dehydrogenase deficiency due to rapid degradation of E1 protein

A mutation of an insertion of 4 bp in the gene for the α subunit of pyruvate dehydrogenase (E1α) was found in a female with pyruvate dehydrogenase deficiency due to the rapid degradation of α and β subunit proteins of pyruvate dehydrogenase. This mutation caused a frameshift that altered the amino acid sequence and created a premature stop codon. This 4-bp insertion has been found in an unrelated female patient with E1α deficiency. It is rare that the same mutation is found in unrelated patients with this rare inborn error of metabolism. Furthermore, short deletions or duplications in the E1α gene of patients with E1α deficiency have been found only in exons 10 and 11. These exons may be hot spots for the mutations by the recombinational processes. This patient was heterozygous for the normal and a mutant allele. However, in most of the cultured skin fibroblasts from this patient, the mutant allele was expressed. These observations suggest that the X chromosome containing the normal allele was predominantly inactivated so that she developed lactic acidaemia and neurological abnormalities despite being heterozygous. The mutant α subunit protein failed to form a stable structure of pyruvate dehydrogenase, so that both α and β subunit proteins were degraded rapidly.