SEVERITY OF MUTATION IN THE PHENYLALANINE-HYDROXYLASE GENE INFLUENCESPHENYLALANINE METABOLISM IN PHENYLKETONURIA AND HYPERPHENYLALANINEMIAHETEROZYGOTES

We examined whether the degree of residual activity from the mutant ph enylalanine hydroxylase (PAH) allele affected phenylalanine metabolism in heterozygotes for phenylketonuria (PKU) or non-PKU hyperphenylalan inaemia (HPA). Discriminant analysis was carried out to find the funct ion of fasting plasma concentrations of phenylalanine (PHE) and tyrosi ne (TYR) that best separated carriers from non-carriers. This function (0.103TYR - 0.214-PHE(CORR) - 4.499) was subsequently used as the dep endent variable, with the in vitro activity of the expressed mutant PA H as the independent variable, in a regression analysis performed on h eterozygotes for mutations that had been studied in a eukaryotic cell expression system. This analysis showed a significant correlation (r = 0.40, n = 140, p < 0.001), although there was a wide spread of values within each of the two major groups of carriers and a considerable ov erlap between the groups. We conclude that the severity of the mutatio n, as determined by in vitro expression analysis, in the mutant PAH ge ne is reflected in the biochemical phenotype of heterozygotes. This re sult emphasizes the relevance of the cell expression system used for e stablishing the relative severities of most mutations at the PAH locus . Differences in the activities from the carried mutant PAH allele on phenylalanine metabolism in heterozygotes are, however, small compared to. the activity from the normal PAH allele and are. easily obscured by other factors leading to inter- or intra-individual variation in ph enylalanine metabolism. Fasting plasma concentrations of phenylalanine and tyrosine thus can not be used to predict the severity of the carr ied PAH mutation in individual PKU or HPA heterozygotes.