Molecular basis of ornithine transcarbamylase deficiency lacking enzyme protein

We report an ornithine transcarbamylase(OTC)-deficient male patient who had no detectable immunoreactive materials but did have active mRNA for OTC-related protein. The total absence of OTC activity in the liver of the patient was caused by a complete lack of immunoreactive material, as determined by Ouchterlony double immunodiffusion, single radial immunodiffusion, and sodium dodecylsulphate-polyacrylamide gel electrophoresis of immunoprecipitate and of liver homogenate. However, mRNA coding for the precursor of OTC was clearly detected in autopsy specimens of the patient's liver as well as of controls in a cell-free translation system consisting of rabbit reticulocyte lysates and [35S]methionine. The labelled precursor of OTC synthesized in vitro with mRNA from the patient could be transported into rat liver and kidney mitochondria and processed to form a protein with a molecular weight indistinguishable from mature OTC, suggesting that there was no defect in the protein structure necessary for its transport into mitochondria. These results suggest that the primary defect of the OTC deficiency was located in the structural gene and that the labile OTC-related protein, after being synthesized with its mRNA, was degraded too rapidly to be detected by the method used.