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PAH
phenylalanine hydroxylase
The PAH gene provides instructions for producing phenylalanine hydroxylase, an enzyme crucial for metabolising the amino acid phenylalanine. The PAH gene encodes the enzyme phenylalanine hydroxylase, which plays a vital role in converting phenylalanine to tyrosine.
PAH is located on the long (q) arm of chromosome 12, at band 12q23.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The PAH gene, or phenylalanine hydroxylase gene, is a key component in the body's metabolic pathways. It directs the synthesis of the phenylalanine hydroxylase enzyme. This enzyme is essential for processing phenylalanine, an amino acid obtained through dietary sources such as meat, eggs, and dairy products. Proper functioning of the PAH enzyme is critical for preventing the harmful accumulation of phenylalanine in the body.
What the gene does
The phenylalanine hydroxylase enzyme, encoded by the PAH gene, is responsible for catalysing a specific biochemical reaction. Its primary role is to convert phenylalanine into another amino acid, tyrosine. This conversion is a crucial step in amino acid metabolism. The enzyme functions with a cofactor called tetrahydrobiopterin (BH4) to facilitate this chemical change. Tyrosine, the product of this reaction, is then used by the body to produce various essential substances, including hormones, the pigment melanin which influences skin and hair colour, and neurotransmitters that transmit signals in the brain. Tyrosine can also be broken down further to generate energy for cellular processes.
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Chromosome location
The PAH gene is situated on chromosome 12, specifically at position 12q23.2. This location refers to the long arm (q) of chromosome 12, within region 23, band 2. The human genome contains two copies of chromosome 12, one inherited from each parent, and the PAH gene is found at this specific locus on both copies.
Protein structure
The phenylalanine hydroxylase protein is composed of 452 amino acids. It features a key regulatory domain known as the ACT domain, located between amino acids 36 and 114. This ACT domain is involved in binding small molecules and plays a role in regulating the enzyme's activity.
Key variants
Hundreds of different genetic changes, or variants, have been identified within the PAH gene. These variants can alter the structure or function of the phenylalanine hydroxylase enzyme, leading to a reduction or complete loss of its activity. The impact of a specific variant on enzyme function can vary, leading to a spectrum of clinical presentations.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1232C>G | p.Ser411Ter | Pathogenic | ★★★☆ | Phenylketonuria |
c.353-2A>T | - | Pathogenic | ★★★☆ | Phenylketonuria |
c.47_48dup | p.Asp17fs | Pathogenic | ★★★☆ | Phenylketonuria |
c.478C>T | p.Gln160Ter | Pathogenic | ★★★☆ | Phenylketonuria |
c.510-19_667del | - | Pathogenic | ★★★☆ | Phenylketonuria |
c.548A>G | p.Glu183Gly | Pathogenic | ★★★☆ | Phenylketonuria |
c.560G>A | p.Trp187Ter | Pathogenic | ★★★☆ | Phenylketonuria |
c.669del | p.Asn223fs | Pathogenic | ★★★☆ | Phenylketonuria |
c.75del | p.Ile25fs | Pathogenic | ★★★☆ | Phenylketonuria |
c.971T>A | p.Ile324Asn | Pathogenic | ★★★☆ | Phenylketonuria |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the PAH gene are primarily associated with Phenylketonuria (PKU). This is an inherited metabolic condition where the body cannot properly break down phenylalanine, leading to its accumulation in the blood. If left untreated, high levels of phenylalanine can be toxic, particularly to the brain, and can cause significant health problems, including intellectual disability.
Inheritance pattern
Conditions caused by pathogenic PAH variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The PAH gene is well-recognised within the UK's clinical genomics landscape. It is listed on several NHS Genomic Medicine Service national panels via PanelApp, including those for DDG2P, Early onset or syndromic epilepsy, Intellectual disability, Leukodystrophy (adult onset), Likely inborn error of metabolism, Phenylketonuria, and Undiagnosed metabolic disorders. Its presence on these 'green' rated panels indicates strong evidence for its gene-disease association in a clinical setting.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is phenylalanine and why is it important to metabolise it?
Phenylalanine is an essential amino acid, meaning it must be obtained through diet. It's a building block for proteins. Proper metabolism of phenylalanine, primarily by the PAH enzyme, is crucial to prevent its buildup to toxic levels, which can negatively affect brain development and function.
How is Phenylketonuria (PKU) inherited?
Phenylketonuria (PKU) is inherited in an autosomal recessive pattern. This means an individual must inherit two altered copies of the PAH gene, one from each parent, to develop the condition. Individuals with only one altered copy are carriers and typically do not show symptoms.
What happens if the PAH enzyme doesn't work correctly?
If the PAH enzyme does not function correctly, phenylalanine cannot be converted to tyrosine. This leads to an accumulation of phenylalanine in the blood. High levels of phenylalanine are particularly harmful to the developing brain, causing the characteristic symptoms of Phenylketonuria if untreated.
References
- Scriver CR. The PAH gene, phenylketonuria, and a paradigm shift. Human mutation. 2007. PMID: 17443661
- Blau N, Erlandsen H. The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Molecular genetics and metabolism. 2004. PMID: 15171997
- Waters PJ. How PAH gene mutations cause hyper-phenylalaninemia and why mechanism matters: insights from in vitro expression. Human mutation. 2003. PMID: 12655545
- Pey AL, Desviat LR, Gámez A. Phenylketonuria: genotype-phenotype correlations based on expression analysis of structural and functional mutations in PAH. Human mutation. 2003. PMID: 12655546
- Güttler F, Azen C, Guldberg P. Impact of the phenylalanine hydroxylase gene on maternal phenylketonuria outcome. Pediatrics. 2003. PMID: 14654659
- Erlandsen H, Patch MG, Gamez A. Structural studies on phenylalanine hydroxylase and implications toward understanding and treating phenylketonuria. Pediatrics. 2003. PMID: 14654665
- Adam MP, Bick S, Mirzaa GM. Phenylalanine Hydroxylase Deficiency. 1993. PMID: 20301677