Identification of seven novel missense mutations, two splice-site mutations, two microdeletions and a polymorphic amino acid substitution in the gene for ornithine transcarbamylase (OTC) in patients with OTC deficiency.

Ornithine transcarbamylase (OTC) deficiency, a X-linked disorder, is the most frequent inborn error of the urea cycle. Point mutations and small deletions/insertions in the OTC gene are responsible for the majority of the cases and have a "private" character with little recurrence. We report on eleven pathological changes in the OTC gene sequence detected in three males with mild clinical presentations, and in eight symptomatic females. All of these mutations are novel. Only one mutation affects a CpG mutational hot spot, whereas all but one of the mutations caused an abnormal SSCP of the corresponding PCR-amplified exon. Two mutations occurring in females involved one or two base deletions in codons 196 and 330, respectively, causing frameshift changes and premature termination. Another two mutations in a female and a male affected acceptor splice sites at bases -1 and -3 of the intron 6/exon 7 and intron 9/exon 10 junctions, respectively. All other mutations were point changes causing the simple amino acid substitutions (M1I, I160S, L191F, M206I, L301F, P305H and L341P), although the mutation M1I may abolish translation of the OTC polypeptide. This mutation coexisted in a female patient with the change T333A that appears to be a previously unreported polymorphism. The three male patients but only four of the eight female patients inherited the mutation.