The mechanism of BH4 -responsive hyperphenylalaninemia--as it occurs in the ENU1/2 genetic mouse model.
The Pah(enu1/enu2) (ENU1/2) mouse is a heteroallelic orthologous model displaying blood phenylalanine (Phe) concentrations characteristic of mild hyperphenylalaninemia. ENU1/2 mice also have reduced liver phenylalanine hydroxylase (PAH) protein content (∼20% normal) and activity (∼2.5% normal). The mutant PAH protein is highly ubiquitinated, which is likely associated with its increased misfolding and instability. The administration of a single subcutaneous injection of l-Phe (1.1 mg l-Phe/g body weight) leads to an approximately twofold to threefold increase of blood Phe and phenylalanine/tyrosine (Phe/Tyr) ratio, and a 1.6-fold increase of both nonubiquitinated PAH protein content and PAH activity. It also results in elevated concentrations of liver 6R-l-erythro-5,6,7,8-tetrahydrobiopterin (BH(4)), potentially through the influence of Phe on GTP cyclohydrolase I and its feedback regulatory protein. The increased BH(4) content seems to stabilize PAH. Supplementing ENU1/2 mice with BH(4) (50 mg/kg/day for 10 days) reduces the blood Phe/Tyr ratio within the mild hyperphenylalaninemic range; however, PAH content and activity were not elevated. It therefore appears that BH(4) supplementation of ENU1/2 mice increases Phe hydroxylation levels through a kinetic rather than a chaperone stabilizing effect. By boosting blood Phe concentrations, and by BH(4) supplementation, we have revealed novel insights into the processing and regulation of the ENU1/2-mutant PAH.
Department of Human Genetics, McGill University-Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada.
Christineh N
CN
Sarkissian
Ming
M
Ying
Tanja
T
Scherer
Beat
B
Thöny
Aurora
A
Martinez
D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006900:Hydroxylation; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010649:Phenylalanine / Q000235:genetics / Q000378:metabolism; D010651:Phenylalanine Hydroxylase / Q000235:genetics* / Q000378:metabolism; D010661:Phenylketonurias / Q000235:genetics*
D001708:Biopterins; D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase; C003402:sapropterin