Phenylalanine Hydroxylase - Disease Relevance

Disease Relevance

Deficiency in PheOH activity due to mutations in the PAH gene causes hyperphenylalaninemia (HPA), and when blood phenylalanine levels increase above 20 times the normal concentration, the metabolic disease phenylketonuria (PKU) results. PKU is both genotypically and phenotypically heterogeneous: Over 300 distinct pathological mutants have been identified, the majority of which correspond to missense mutations that map to the catalytic domain. When a cohort of identified PheOH mutants were expressed in recombinant systems, the enzymes displayed altered kinetic behavior and/or reduced stability, consistent with structural mapping of these mutations to both the catalytic and tetramerization domains of the enzyme. Interestingly, BH4₄ has been administered as a pharmacological treatment and has been shown to reduce blood levels of phenylalanine for a segment of PKU patients whose genotypes lead to some residual PAH activity but have no defect in BH4₄ synthesis or regeneration. Follow-up studies suggest that in the case of certain PheOH mutants, excess BH4₄ acts as a pharmacological chaperone to stabilize mutant enzymes with disrupted tetramer assembly and increased sensitivity to proteolytic cleavage and aggregation. Mutations that have been identified in the PAH locus are documented at the Phenylalanine Hydroxylase Locus Knowledgbase (PAHdb, http://www.pahdb.mcgill.ca/).

Since phenylketonurea can cause irreversible damage, it is imperative that deficiencies in the Phenylalanine Hydroxylase are determined early on in development. One method is a post-parturition screening test known as the Guthrie Test. The common method is via drawing blood from a small needle prick at the heel of the newborn and testing it for phenylketonurea, indicative of a PH deficiency. Placing the individual on a low phenylalanine, high tyrosine diet can help prevent any long-term damage to their development.