Phenylalanine hydroxylase gene (PAH) (PAH)

The Phenylalanine hydroxylase (PAH) gene locus in hepatocytes is the primary genomic target for curative interventions in Phenylketonuria (PKU), a metabolic disorder characterized by the body's inability to metabolize the amino acid phenylalanine (NCBI Gene: 5053). Located on chromosome 12q23.2, this locus encodes the PAH enzyme, which is predominantly expressed in the liver and is responsible for converting phenylalanine to tyrosine (UniProt: P00439). Mutations within this genomic region lead to toxic phenylalanine accumulation, resulting in severe cognitive impairment and neurological damage if not managed by a strict low-protein diet (PubMed: 29059072). Therapeutic approaches targeting this DNA locus include gene addition via adeno-associated virus (AAV) vectors, such as HMI-102 and BMN 307, which deliver a functional PAH transgene to hepatocytes (ClinicalTrials.gov: NCT03952156). More recently, gene editing technologies like CRISPR/Cas9 and base editors are being developed to permanently correct endogenous mutations directly at the PAH locus (PubMed: 30337430). These genomic therapies aim to restore long-term enzymatic activity and normalize blood phenylalanine levels, potentially offering a one-time cure for patients. However, challenges remain regarding the precision of DNA modifications, the risk of insertional mutagenesis, and the potential for host immune responses against delivery vehicles (PubMed: 31263283).

Other names

PAH genePhenylalanine 4-monooxygenase gene12q23.2 locusPhenylalanine hydroxylase locus

Gene addition or gene editing to restore functional phenylalanine hydroxylase expression.