The PAH gene provides instructions for making an enzyme called phenylalanine hydroxylase. This enzyme is responsible for the first step in processing phenylalanine, which is a building block of proteins (an amino acid) obtained through the diet. Phenylalanine is found in all proteins and in some artificial sweeteners.
Phenylalanine hydroxylase is responsible for the conversion of phenylalanine to another amino acid, tyrosine. The enzyme works with a molecule called tetrahydrobiopterin (BH4) to carry out this chemical reaction. Tyrosine is used to make several types of hormones, certain chemicals that transmit signals in the brain (neurotransmitters), and a pigment called melanin, which gives hair and skin their color. Tyrosine can also be broken down into smaller molecules that are used to produce energy.
Health Conditions Related to Genetic Changes
More than 500 mutations in the PAH gene have been identified in people with phenylketonuria (PKU). Most of these mutations change single amino acids in phenylalanine hydroxylase. For example, the most common mutation in many populations replaces the amino acid arginine with the amino acid tryptophan at position 408 (written as Arg408Trp or R408W). Other PAH mutations delete small amounts of DNA from the gene or disrupt the way the gene's instructions are used to make phenylalanine hydroxylase.
PAH mutations reduce the activity of phenylalanine hydroxylase, preventing it from processing phenylalanine effectively. As a result, this amino acid can build up to toxic levels in the blood and other tissues. Because nerve cells in the brain are particularly sensitive to phenylalanine levels, excessive amounts of this substance can cause brain damage.
Classic PKU, the most severe form of the disorder, occurs when phenylalanine hydroxylase activity is severely reduced or absent. People with untreated classic PKU have levels of phenylalanine high enough to cause severe brain damage and other serious medical problems. Mutations in the PAH gene that allow the enzyme to retain some activity result in milder versions of this condition, such as variant PKU or non-PKU hyperphenylalaninemia.More About This Health Condition
Other Names for This Gene
- L-Phenylalanine,tetrahydrobiopterin:oxygen oxidoreductase (4-hydroxylating)
- Phenylalanine 4-Hydroxylase
- Phenylalanine 4-Monooxygenase
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Blau N, Erlandsen H. The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Mol Genet Metab. 2004 Jun;82(2):101-11. doi: 10.1016/j.ymgme.2004.03.006. Citation on PubMed
- Erlandsen H, Patch MG, Gamez A, Straub M, Stevens RC. Structural studies on phenylalanine hydroxylase and implications toward understanding and treating phenylketonuria. Pediatrics. 2003 Dec;112(6 Pt 2):1557-65. Citation on PubMed
- Guttler F, Azen C, Guldberg P, Romstad A, Hanley WB, Levy HL, Matalon R, Rouse BM, Trefz F, de la Cruz F, Koch R. Impact of the phenylalanine hydroxylase gene on maternal phenylketonuria outcome. Pediatrics. 2003 Dec;112(6 Pt 2):1530-3. Citation on PubMed
- Pey AL, Desviat LR, Gamez A, Ugarte M, Perez B. Phenylketonuria: genotype-phenotype correlations based on expression analysis of structural and functional mutations in PAH. Hum Mutat. 2003 Apr;21(4):370-8. doi: 10.1002/humu.10198. Citation on PubMed
- Regier DS, Greene CL. Phenylalanine Hydroxylase Deficiency. 2000 Jan 10 [updated 2017 Jan 5]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from http://www.ncbi.nlm.nih.gov/books/NBK1504/ Citation on PubMed
- Scriver CR. The PAH gene, phenylketonuria, and a paradigm shift. Hum Mutat. 2007 Sep;28(9):831-45. doi: 10.1002/humu.20526. Citation on PubMed
- Waters PJ. How PAH gene mutations cause hyper-phenylalaninemia and why mechanism matters: insights from in vitro expression. Hum Mutat. 2003 Apr;21(4):357-69. doi: 10.1002/humu.10197. Citation on PubMed