Phenylalanine hydroxylase gene in psychiatric patients: screening and functional assay of mutations

Abstract Background Reports relating phenylalanine kinetics and metabolism to psychiatric disorders led us to undertake the comprehensive screening of the phenylalanine hydroxylase (PAH) coding region and functional testing of discovered mutations in a sample of psychiatric patients and healthy control subjects. Methods Genomic DNA from psychiatric patients and control subjects was assayed for sequence variants in all PAH coding regions and splice junctions. In vivo functional analysis of mutations was conducted by assessing the kinetics and conversion to tyrosine of a standardized phenylalanine dose and by measuring fasting pterin levels. Results A known missense mutation was observed in a schizoaffective subject, and a novel missense mutation was discovered in four subjects with schizophrenia and one normal subject. The schizoaffective patient heterozygous for the known A403V mutation showed the lowest rate of phenylalanine kinetics and lowest conversion to tyrosine in the patient sample. The four schizophrenic patients heterozygous for the novel K274E mutation showed significantly decreased phenylalanine kinetics, reduced conversion to tyrosine, and increased synthesis of the PAH cofactor tetrahydrobiopterin compared with schizophrenic subjects without the mutation. Conclusions The study findings suggest that larger scale studies are warranted to test the relationship of the PAH genotype with a psychiatric phenotype.