The ornithine transcarbamylase (OTC) gene: mutations in 50 Japanese families with OTC deficiency.

Mutations in the OTC gene in 50 Japanese families with OTC deficiency were reviewed in relation to the phenotype of the patients and predicted structure of the mutant enzyme. Similar to other X-linked diseases, mutant alleles in OTC deficiency are highly heterogeneous. Mutations observed in male patients with neonatal onset of the disease included base insertion/deletion, exon skipping, and nonsense and missense mutations in exon 4, 5, 6, or 7. OTC activity was essentially undetectable in this group of patients. These mutations possibly resulted in unstable mRNA or truncated protein, or involved the active site or core domain of the enzyme leading to structural changes. In male patients with late onset, abnormalities observed were missense mutations in exons 2, 4, 8, 9, and 10, and missense mutations plus donor site errors involving exons 4, 5, and 6. OTC activity in these patients was 8.1 +/- 6.3% of the control and most mutations occurred on the surface of the protein. In female patients, age at onset ranged from 19 months to 7 years, depending on residual OTC activities (4.5 to 33% of the control). Most mutations in this group were similar to those seen in male patients with neonatal onset, i.e., nonsense and missense mutations in exons 5 and 6, and exon skipping, leading to null enzyme activity. These collective data can serve for genetic counseling and monitoring in prenatal care.