ORNITHINE TRANSCARBAMYLASE DEFICIENCY - NEW SITES WITH INCREASED PROBABILITY OF MUTATION

Ornithine transcarbamylase (OTC) deficiency, the most common inborn er ror of the urea cycle, shows an X-linked inheritance with frequent new mutations. Investigations of patients with OTC deficiency have indica ted an overproportionate share of mutations at CpG dinucleotides. Thes e 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 defici ency, for new sites with an increased probability of mutation by compl ete DNA sequence analysis of all ten exons of the OTC gene. In six pat ients, two codons in exons 2 and 5, respectively, contained novel recu rrent mutations, all of them affecting CpG dinucleotides. They include d C to T and G to A transitions in codon 40, changing an arginine to c ysteine 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 thi rd mutation showed a more severe phenotypic expression. In addition to these novel mutations, we identified four patients with the known R27 7W mutation, making it the most common point mutation of the OTC gene.