MUTATION OF ORNITHINE TRANSCARBAMYLASE (H136R) IN A GIRL WITH SEVERE INTERMITTENT OROTIC ACIDURIA BUT NORMAL ENZYME-ACTIVITY

Ornithine transcarbamylase deficiency shows X-linked inheritance with partial dominant expression in carrier females. We studied a girl with intermittent severe erotic aciduria and mild hyperammonaemia despite apparently normal enzyme activity in the liver. Sequence analysis of a ll 10 exons of the ornithine transcarbamylase gene revealed a novel A- ->G exchange (A502G) in exon 5 which changes His-136 to arginine in th e ornithine transcarbamylase protein. K-m values for carbamyl phosphat e and ornithine determined in the patient's liver were comparable to t hose of wild-type enzyme but, unlike the wild-type enzyme, the mutant enzyme was unstable upon freezing and thawing. Electron microscopy rev ealed several giant mitochondria with paracrystalline inclusions. The results are compatible with the assumption that the mutant enzyme cann ot form a functional complex with carbamyl phosphate synthetase and th e ornithine carrier resulting in decreased availability of substrates and diminished enzyme activity in vivo.