THE MOLECULAR-BASIS FOR THE 2 DIFFERENT CLINICAL PRESENTATIONS OF CLASSICAL PYRUVATE-CARBOXYLASE DEFICIENCY

Abstract

Eight cases of isolated human pyruvate carboxylase deficiency were examined from 7 families. Although all patients presented with a chronic lacticacidemia, 2 particular patients presented with the added features of hyperammonemia, citrullinemia and hyperlysinemia. When cultured skin fibroblasts from these patients were examined for their ability to synthesize [3H]biotin-containing proteins, the 2 patients who presented with hyperammonemia, citrullinemia and hyperlysinemia did not synthesize a protein of the correct subunit MW (125 K daltons) corresponding to pyruvate carboxylase. When skin fibroblast proteins were labeled with [35S]Met, cross-reacting material (CRM) corresponding to pyruvate carboxylase was immunoprecipitated by antipyruvate carboxylase antiserum in most patients, but again the 2 patients with the atypical presentation showed no CRM. The different clinical presentation of human pyruvate carboxylase deficiency may be a manifestation of 2 different mutations in the pyruvate carboxylase gene, one that results in the synthesis of a relatively inactive pyruvate carboxylase protein CRM (+ ve) and one that results in the lack of expression of the gene in the form of a recognizable protein CRM (- ve).