573 HETEROZYGOTE EXPRESSION IN PROPIONYL CoA CARBOXYLASE (PCC) DEFICIENCY: DIFFERENCES BETWEEN THE MAJOR COMPLEMENTATION GROUPS

Abstract

PCC deficiency, an autosomal recessively inherited disorder, constitutes at least two major genetic complementation groups (A and C) each characterized by the presence of structurally altered PCC. We now report studies of PCC activity in tissue extracts from controls and obligate heterozygotes from both complementation groups. PCC activity in fibroblast extracts from 6 group A heterozygotes was 43-64% of that in control extracts (p<0.001), while activity in 12 group C heterozygotes was indistinguishable from control values. Similar results were obtained using peripheral blood leukocytes. In none of 8 families (5 group C; 3 group A) in which PCC activity was studied in both parents of an affected child were significant differences observed between parents. Thermostability (45°C) of PCC activity in heterozygotes from both groups was identical to control. Activities of two other mitochondrial enzymes (β-methylcrotonyl CoA carboxylase and glutamate dehydrogenase) were comparable in controls and both groups of heterozygotes. Whereas the data from group A heterozygotes conforms to expected gene-dose effects, the results from group C heterozygotes are distinctly unusual. Since mammalian PCC is a tetramer, the latter results may reflect any of the following mechanisms: normal PCC activity in tetramers with at least one normal subunit; an increased proportion of normal subunits due to increased degradation of mutant subunits; or compensatory synthesis of normal subunits.