HUMAN PHENYLALANINE-HYDROXYLASE MUTATIONS AND HYPERPHENYLALANINEMIA PHENOTYPES - A METANALYSIS OF GENOTYPE-PHENOTYPE CORRELATIONS

We analyzed correlations between mutant genotypes at the human phenyla lanine hydroxylase locus (gene symbol PAH) and the corresponding hyper phenylalaninemia (HPA) phenotypes (notably, phenylketonuria [OMIM 2616 00]). We used reports, both published and in the PAH Mutation Analysis Consortium Database, on 365 patients harboring 73 different PAH mutat ions in 161 different genotypes. KPA phenotypes were classified as phe nylketonuria (PKU), variant PKU, and non-PKU HPA. By analysis both of homoallelic mutant genotypes and of ''functionally hemizygous'' hetero allelic genotypes, we characterized the phenotypic effect of 48 of the 73 different, largely missense mutations. Among those with consistent in vivo expression, 24 caused PKU, 3 caused variant PKU, and 10 cause d non-PKU HPA. However, 11 mutations were inconsistent in their effect : 9 appeared in two different phenotype classes, and 2 (I65T and Y414C ) appeared in all three classes. Seven mutations were inconsistent in phenotypic effect when in vitro (unit-protein) expression was compared with the corresponding in vivo phenotype (an emergent property). We c onclude that the majority of PAH mutations confer a consistent phenoty pe and that this is concordant with their effects, when known, predict ed from in vitro expression analysis. However, significant inconsisten cies, both between in vitro and in vivo phenotypes and between differe nt individuals with similar PAH genotypes, reveal that the HPA-phenoty pe is more complex than that predicted by Mendelian inheritance of all eles at the PAH locus.