PAH Gene (Phenylalanine Hydroxylase): Function, Mutations, and Associated Diseases
Comprehensive biomedical overview of the PAH gene, including genomic context, expression, pathogenic variants, and clinical significance in phenylketonuria.
Gene Information Card
| Symbol | PAH |
|---|---|
| Full Name | Phenylalanine hydroxylase |
| Gene Type | protein-coding |
| Chromosomal Location | 12q23.2 |
| NCBI Gene ID | 5053 ncbi.nlm.nih.gov/gene/5053 |
| Ensembl ID | ENSG00000171759 |
| UniProt ID | P00439 |
| OMIM ID | 612349 |
| HGNC ID | 8582 |
| Aliases | PKU, phenylalanine-4-hydroxylase |
Description
The PAH gene encodes phenylalanine hydroxylase, an enzyme that catalyzes the conversion of L-phenylalanine to L-tyrosine using tetrahydrobiopterin (BH4) and molecular oxygen as cofactors. This reaction is the rate-limiting step in the catabolism of phenylalanine. Mutations in PAH lead to phenylketonuria (PKU) and other forms of hyperphenylalaninemia, characterized by elevated phenylalanine levels in blood and tissues, which can cause intellectual disability if untreated. The enzyme is primarily expressed in the liver and kidney.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Phenylketonuria (PKU) | Loss-of-function mutations in PAH reduce or abolish enzyme activity, leading to accumulation of phenylalanine and its metabolites, causing neurotoxicity. | ClinVar, OMIM |
| Hyperphenylalaninemia, non-PKU | Milder mutations cause partial enzyme deficiency, resulting in moderate elevation of phenylalanine without severe clinical phenotype. | ClinVar, OMIM |
| Maternal phenylketonuria | Mutations in the mother cause elevated phenylalanine during pregnancy, leading to fetal developmental abnormalities. | OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | High (nTPM ~ 200) | Primary site of expression |
| Kidney | Moderate (nTPM ~ 20) | Secondary expression |
| Brain | Low (nTPM < 1) | Minimal expression |
| Small intestine | Low (nTPM < 1) | Trace expression |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 (liver carcinoma) | High | Used as model for hepatic expression |
| HEK293 (embryonic kidney) | Moderate | Transfected for functional studies |
| HeLa (cervical carcinoma) | Low | Not endogenously expressed |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1222C>T (p.Arg408Trp) | Missense | Common (allele frequency ~10-20% in PKU) | Severe enzyme deficiency, classic PKU |
| c.782G>A (p.Arg261Gln) | Missense | Common (allele frequency ~5-10%) | Moderate to severe deficiency |
| c.842C>T (p.Pro281Leu) | Missense | Common (allele frequency ~5%) | Variable severity, often mild |
| c.1066-11G>A (IVS10-11G>A) | Splicing | Common (allele frequency ~5%) | Splicing defect, severe phenotype |
| c.168+5G>T (IVS2+5G>T) | Splicing | Less common | Splicing defect, severe |
Mutation functional classification
Loss of Function (LOF)
Most PAH mutations are loss-of-function, reducing or eliminating enzyme activity. This leads to phenylalanine accumulation and PKU.
Gain of Function (GOF)
No gain-of-function mutations have been reported for PAH.
Dominant Negative (DN)
PAH is a homotetramer; some missense mutations may exert a dominant-negative effect by disrupting tetramer assembly, but this is rare and not well established.
View complete mutation data：
Gene Ontology (GO)
Pathways
• Phenylalanine metabolism (KEGG: hsa00360)
• Tyrosine metabolism (KEGG: hsa00350)
• Tetrahydrobiopterin (BH4) metabolism
Protein Summary
Phenylalanine hydroxylase (PAH) is a homotetrameric enzyme, each subunit containing a catalytic domain and a regulatory domain. It requires iron and tetrahydrobiopterin (BH4) as cofactors. The enzyme is allosterically regulated by phenylalanine and inhibited by its cofactor BH4. Deficiency leads to PKU, treatable by dietary restriction of phenylalanine and BH4 supplementation in some cases.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| PAH Knockout HEK293 Cell Line | EDJ-KQ3979 | Human | 5053 | Details Get a Quote |
| PAH Knockout HeLa Cell Line | EDJ-KQ54074 | Human | 5053 | Details Get a Quote |
| PAH Knockout A-549 Cell Line | EDJ-KQ62562 | Human | 5053 | Details Get a Quote |
| PAH Knockout HCT 116 Cell Line | EDJ-KQ71032 | Human | 5053 | Details Get a Quote |
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