This report describes phenylketonuria, which is an amino acid metabolic disorder. The human gene implicated is PAH, which encodes phenylalanine hydroxylase. There is one high-scoring fly ortholog, Dmel\Hn, for which multiple genetic reagents, including classical alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
The human gene PAH has not been introduced into flies.
Ubiquitous RNAi knockdown of Dmel\Hn results in elevated bodily phenylalanine levels. Affected larvae show increased sensitivity to extra levels of phenylalanine, but not to other large neutral amino acids, resulting in larval death. Affected individuals also display movement defects. Similar phenotypes are observed in fat body-specific RNAi knockdown of Dmel\Hn. Phenylalanine sensitivity of PKU flies could be modulated with dietary iron, and the eclosion defect could be almost entirely rescued by treatment with tyrosine and L-DOPA.
[updated Aug. 2026 by FlyBase; FBrf0222196]
[PHENYLKETONURIA; PKU](https://omim.org/entry/261600)
[PHENYLALANINE HYDROXYLASE; PAH](https://omim.org/entry/612349)
Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase (PAH), an enzyme that catalyzes the hydroxylation of phenylalanine to tyrosine, the rate-limiting step in phenylalanine catabolism. If undiagnosed and untreated, phenylketonuria can result in impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia (Zurfluh et al., 2008, pubmed:17935162). [from MIM:261600; 2026.08.21]
Phenylketonuria (PKU) and non-PKU mild hyperphenylalaninemia (HPA) are caused by homozygous or compound heterozygous mutations in the PAH gene on chromosome 12q23. [from MIM:261600; 2026.08.21]
Phenylalanine hydroxylase (PAH) catalyzes the hydroxylation of phenylalanine to tyrosine, the rate-limiting step in phenylalanine catabolism. The reaction is dependent on tetrahydrobiopterin (BH4), as a cofactor, molecular oxygen, and iron. [from MIM:612349; 2026.08.21]
High-scoring ortholog of human PAH; moderate-scoring ortholog of human TPH1 and TPH2 (3 Drosophila to 3 human).
