Molecular Mechanism of Late Onset Type of Ornithine Transcarbamylase Deficiency in Males

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Mutation analysis of ornithine transcarbamylase (OTC) gene in adolescent and adult male patients with OTC deficiency revealed a mutation that changes arginine at codon 40 to histidine (R40H) in 6 patients from 5 families and another one converting tyrosine at codon 55 to aspartate (Y55D) in one patient. Expression experiment using Cos-1 cells revealed that the R40H and Y55D mRNA levels were similar to that of wild-type OTCmRNA,so was OTC mRNA in liver tissue of one R40H patient, indicating that at least R40H OTC is normally spliced and as stable as wild-type mRNA.The activities of R40H and Y55D OTC's in the transfected Cos-1 cells were, however, reduced to 28% of that of wild-type OTC and the amounts of cross reactive material were reduced in both mutant OTC's. The activity of R40H OTC lecreased to 5.5% of the wild-type OTC when it was treated by five cycles of freezing and thawing, indicating instability of the mutant OTC protein. In contrast, Y55D OTC did not decrease after the treatment. Apparent Km values and pH-activity profile were studied in liver tissue of one R40H patient. These were comparable to those of normal enzyme. These results suggest that the mechanism (s) of enzyme deficiency in R40H mutation involve accelerated degradation due to instability of the mutant OTC,inadequate mitochondrial localization of the preOTC or both. The mechanism of deficiency of Y55D OTC remains to be elucidated. In one family, transmission of R40H gene from a father to a daughter was documented. This paternal transmission of R40HOTC gene may render it to be retained in general population more frequently than those associated with early onset disease which are exclusively transmitted throught maternal lineage.