Pah-R243Q Mouse

Phenylalanine hydroxylase (PAH) is a member of the biotin-dependent aromatic amino acid hydroxylase protein family encoded by the PAH gene. The main function of PAH is to hydroxylate phenylalanine (Phe) into tyrosine (Tyr), a crucial step in phenylalanine catabolic metabolism. Lack of PAH activity can lead to the autosomal recessive inherited disorder phenylketonuria (PKU), also known as PAH deficiency. PKU is a congenital disease caused by pathogenic variants in the PAH gene and belongs to the group of amino acid metabolic disorders. Patients with PKU excrete large amounts of phenylketones and other metabolites in their urine. In PKU patients, deficiency of the PAH enzyme results in elevated blood phenylalanine (Phe) levels, leading to brain dysfunction. Untreated PKU patients may experience severe and irreversible intellectual disabilities, seizures, behavioral disturbances, microcephaly, epilepsy, psychological symptoms, and generalized hypopigmentation of the skin (including hair and eyes). Approximately 1 in 24,000 individuals is affected by PKU ^[1-2]. R243Q is a high-frequency mutation site in East Asian/Asian PKU patients. This mutation is located in exon 7 of the PAH gene and results in the amino acid at position 243 changing from arginine (R) to glutamine (Q) ^[3-4]. In vitro experiments have confirmed that the activity and expression levels of the defective PAH protein based on the R243Q mutation can be modulated, suggesting that this site has the potential to be a therapeutic target for PKU ^[5].

Pah-R243Q mice are obtained by introducing the R243Q mutation into the mouse Pah gene using gene editing technology. Pah-R243Q mice serve as valuable tools for studying the genetic mechanisms of PKU in humans and for the preclinical evaluation of therapeutic drugs.