BIOTIN-RESPONSE ORGANIC-ACIDURIA - MULTIPLE CARBOXYLASE DEFECTS AND COMPLEMENTATION STUDIES WITH PROPIONICACIDEMIA IN CULTURED FIBROBLASTS

Fibroblast cultures from two individuals with biotin-responsive organicacidemia were found to have a pleiotropic deficiency of propionyl-CoA carboxylase, β-methylcrotonyl-CoA carboxylase, and pyruvate carboxylase activities after growth in biotin limited culture medium, conditions which do not affect the carboxylase activities of normal cells. All three enzyme activities were restored to normal levels after transferring the mutant strains to biotin-rich medium. Both patients excreted abnormal levels of an array of metabolic intermediates, including β-methylcrotomate, β-hydroxyisovalerate, β-hydroxypropionate, and lactate, which reflect metabolic blocks at all three carboxylase sites. 14 mutants deficient in only propionyl-CoA carboxylase activity from patients with propionicacidemia and the two biotin-responsive strains were examined for complementation with seven previously mapped pcc mutants. No new pcc complementation groups were identified. Nine of the mutants were mapped to group pccA. The remaining 12 mutants mapped to pccBC or its B or C subgroups, confirming the complex nature of this group. The biotin-responsive mutants failed to complement each other but did complement mutants from all the pcc groups. Thus biotin-responsive organicacidemia is defined by a new complementation group, bio. The results obtained in this study suggest that the bio mutants have a defect of either biotin transport or a common holocarboxylase synthetase required for the biotin activation of all three mitochondrial carboxylases.