MUTATION IN THE 4A-CARBINOLAMINE DEHYDRATASE GENE LEADS TO MILD HYPERPHENYLALANINEMIA WITH DEFECTIVE COFACTOR METABOLISM

Hyperphenylalaninemias represent a major class of inherited metabolic disorders. They are most often cause by mutations in the phenylalanine hydroxylase gene and, less frequently but with usually more serious c onsequences, in genes necessary for the synthesis and regeneration of the cofactor, tetrahydrobiopterin. This cofactor is absolutely require d for all aromatic amino acid hydroxylations, and, recently, nitric ox ide production from L-arginine has also been found to be dependent on tetrahydrobiopterin. Phenylalanine hydroxylase catalyzes a coupled rea ction in which phenylalanine is converted to tyrosine and in which tet rahydrobiopterin is converted to the unstable carbinolamine, 4a-hydrox ytetrahydrobiopterin. The enzyme, carbinolamine dehydratase, catalyzes the dehydration of the carbinolamine to quinonoid dihydropterin. A de creased rate of dehydration of this compound has been hypothesized to be responsible for the production of 7-biopterin found in certain mild ly hyperphenylalaninemic individuals. We have now identified nonsense and missense mutations in the 4a-carbinolamine dehydratase gene in a h yperphenylalaninemic child who excretes large amounts of 7-biopterin. This finding is consistent with the role of the carbinolamine dehydrat ase in the phenylalanine hydroxylation reaction. Together with previou sly identified inherited disorders in phenylalanine hydroxylase and di hydropteridine reductase, there are now identified mutations in the th ree enzymes involved in the phenylalanine hydroxylation system. In add ition, the genetics of this system may have broader implications, sinc e the product of the dehydratase gene has previously been shown to pla y an additional role (as dimerization cofactor for hepatocyte nuclear factor-1alpha) in the regulation of transcription, through interaction with hepatocyte nuclear factor-1alpha.