DEMONSTRATION OF THE SPF-ASH MUTATION IN SPANISH PATIENTS WITH ORNITHINE TRANSCARBAMYLASE DEFICIENCY OF MODERATE SEVERITY

We have found in patients with ornithine transcarbamylase (OTC) defici ency from two Spanish families (A and B), replacement by A of G at the 3'-end of exon 4 of the OTC gene. The same mutation is found in the s pf-ash mouse, a rodent model of mild OTC deficiency, causing a neutral R129H mutation and inefficient splicing at the 5' donor site of the e xon 4-intron 4 junction, with resultant 4%-7% residual OTC activity. T he mutation, detected in our patients using polymerase chain reaction (PCR) amplification of the ten OTC exons, single strand conformation p olymorphism (SSCP) analysis and direct sequencing of PCR-amplified exo n 4, results in the loss of a unique MspI restriction site which can b e used for rapid diagnosis. The mutation was transmitted by the mother in family A and arose de novo in the patient in family B. Residual OT C activity, determined in a male and a female patient, was 1.3% and 3. 5% of normal, respectively. Despite this low activity, the surviving p atients have developed normally.