Genetic defects in human pyruvate dehydrogenase.

The nature of PDC deficiency has been characterized at the levels of total and component catalytic activities as well as at the levels of component proteins and specific mRNAs. Defects in 14 cases were shown to involve the E1 component, and there was one case each of an apparent E2 and E3 deficiency. Defects involving the E1 component exhibit heterogeneous expression of E1 proteins and mRNAs, indicating that different types of mutations cause E1 deficiency. E1 deficiencies can occur either in the presence or absence of E1 proteins, representing catalytic mutations or mutations affecting the expression of E1 proteins, respectively. In every case where the content of E1 proteins is reduced, both the E1 alpha and the E1 beta peptides are simultaneously affected. This is likely to be due to rapid degradation of any E1 peptide that is not complexed into the alpha 2 beta 2 conformation. Among subjects with reduced levels of both E1 peptides, some had normal amounts of specific E1 alpha and E1 beta mRNAs. In these subjects, the primary mutations affect either translational or post-translational processes leading to the formation of mature E1 proteins in the mitochondria. In contrast, two cases of simultaneous reduction of both E1 alpha and E1 beta proteins had decreases in the amounts of E1 alpha mRNA only. Mutations in these cases may impair the transcription, nuclear processing, or stability of E1 alpha mRNA. E1 deficiency may manifest in a variable manner. Further characterization of this phenomenon might provide insight into the discrepancy between the clinical severity of the defect and the residual level of PDC catalytic activity. Available information indicates that the E1 alpha gene is located on the X chromosome, but sex distribution of E1 alpha defects suggests that the mode of inheritance may not follow a simple X-linked pattern. The availability of specific PDC antibodies and cDNA clones, as well as the application of molecular biological techniques, should facilitate the characterization of the molecular basis of various PDC deficiencies. This information should provide better understanding of the function of PDC, pathophysiology of PDC deficiency, and mechanisms of inheritance and expression of these genes.