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The mechanism of BH 4 ‐responsive hyperphenylalaninemia—As it occurs in the ENU1/2 genetic mouse model
Author(s) -
Sarkissian Christineh N.,
Ying Ming,
Scherer Tanja,
Thöny Beat,
Martinez Aurora
Publication year - 2012
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22128
Subject(s) - phenylalanine hydroxylase , phenylalanine , tetrahydrobiopterin , hyperphenylalaninemia , biology , endocrinology , medicine , mutant , tyrosine , biopterin , biochemistry , amino acid , enzyme , cofactor , gene
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. Hum Mutat 33:1464–1473, 2012. © 2012 Wiley Periodicals, Inc.