We report 7 patients with pyruvate dehydrogenase (PDH) deficiency caused by mutations of the PDH-E1⍺ subunit. Each patient had a different mutation; 4 with duplicate insertions, 1 with a deletion of tandem repeat, and 2 with point mutations. Five of the mutations were novel, thus confirming allelic heterogeneity. Immunoblot analysis revealed decreased immunoreactivity for the E1⍺ and E1β subunits in every patient. Pulse-labeling and chase study of the E1⍺ and E1β subunits revealed that initial synthesis of the mutant E1⍺ subunit was normal and posttranslational degradation was complete by 48 hours. However, the post-translational degradation rate of the E1β subunit varied from one patient to another. Factors other than instability of the E1β monomer must contribute to the degradation rate of this subunit in the presence of an E1⍺ subunit mutation. Including this series, 3 patients with thhe S312 deletion and 5 with the R302C point mutation have been reported, and all of these patients are female. These findings suggest that these two loci are hot spots for gene mutations, and may be lethal in the male fetus.
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Publié par Elsevier Masson SAS.