Ornithine transcarbamylase deficiency: new sites with increased probability of mutation.

Ornithine transcarbamylase (OTC) deficiency, the most common inborn error of the urea cycle, shows an X-linked inheritance with frequent new mutations. Investigations of patients with OTC deficiency have indicated an overproportionate share of mutations at CpG dinucleotides. These statistics may, however, be biased because of the easy detection of CpG mutations by screening for TaqI and MspI restriction sites. In the present study, we investigated 30 patients, with diagnosed OTC deficiency, for new sites with an increased probability of mutation by complete DNA sequence analysis of all ten exons of the OTC gene. In six patients, two codons in exons 2 and 5, respectively, contained novel recurrent mutations, all of them affecting CpG dinucleotides. They included C to T and G to A transitions in codon 40, changing an arginine to cysteine and histidine, respectively, and a C to T transition in codon 178 causing the substitution of threonine by methionine. The first two mutations were characterized by a mild clinical course with high risk of sudden death in late childhood or early adulthood, whereas the third mutation showed a more severe phenotypic expression. In addition to these novel mutations, we identified four patients with the known R277W mutation, making it the most common point mutation of the OTC gene.