Evidence for mutational cis-acting factors affecting mutagenesis in the ornithine transcarbamylase gene

Ornithine transcarbamylase (OTC; EC 2.1.3.3) is an urea cycle enzyme coded by a gene located at Xp21.1. The genetic deficiency is caused by a wide spectrum of pathological mutations, most of them occurring de novo. Using two (CA)n flanking markers of the OTC gene (DXS997 and DXS1068), we have defined the haplotypic background underlying 37 different mutational events and compared the results with a random sample of control chromosomes (N=141) from Iberia Peninsula. The allelic distribution of the (CA)n markers revealed significant differences between affected and non-affected chromosomes. One particular haplotypic combination can be considered as a risk factor for carrying OTC mutations, with a relative risk of 13.3 (95% confidence interval 2.89-61.5, p=1.5 x 10(-5)). Since most of pathogenic OTC mutations are short-lived or de novo, these findings strongly support the hypothesis that a specific haplotypic background confers a higher risk for mutation occurrence at this locus.