The PAH gene provides instructions for making an enzyme called phenylalanine hydroxylase. This enzyme helps process phenylalanine, which is a building block of proteins (amino acid). Phenylalanine is obtained through the diet; it is found in certain foods (such as meat, eggs, nuts, and milk) 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 and a pigment called melanin, which gives hair and skin their color. It is also used to make neurotransmitters, which are chemicals that transmit signals in the brain. Tyrosine can also be broken down into smaller molecules that are used to produce energy.
Health Conditions Related to Genetic Changes
Hundreds of variants (also called mutations) in the PAH gene have been identified in people with phenylketonuria (PKU). This condition increase the levels of phenylalanine in the blood. If PKU is not treated, phenylalanine can build up to harmful levels, causing intellectual disability and other serious health problems.
Most of the variants that cause PKU change single amino acids in phenylalanine hydroxylase. For example, the most common variant in many populations replaces the amino acid arginine with the amino acid tryptophan at position 408 (written as Arg408Trp or R408W) in phenylalanine hydroxylase. Other PAH gene variants delete small amounts of DNA from the gene or disrupt the way the gene's instructions are used to make phenylalanine hydroxylase.
PAH gene variants 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 in people who have very low levels of phenylalanine hydroxylase activity or who have no phenylalanine hydroxylase activity at all. People with untreated classic PKU have levels of phenylalanine high enough to cause severe brain damage and other serious medical problems. Variants 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
- Elhawary NA, AlJahdali IA, Abumansour IS, Elhawary EN, Gaboon N, Dandini M, Madkhali A, Alosaimi W, Alzahrani A, Aljohani F, Melibary EM, Kensara OA. Genetic etiology and clinical challenges of phenylketonuria. Hum Genomics. 2022 Jul 19;16(1):22. doi: 10.1186/s40246-022-00398-9. 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, Feldman J, 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