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The mechanism of BH4-responsive hyperphenylalaninemia—As it occurs in the ENU1/2 genetic mouse model


Sarkissian, Christineh N; Ying, Ming; Scherer, Tanja; Thöny, Beat; Martinez, Aurora (2012). The mechanism of BH4-responsive hyperphenylalaninemia—As it occurs in the ENU1/2 genetic mouse model. Human Mutation, 33(10):1464-1473.

Abstract

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.

Abstract

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2012
Deposited On:16 Nov 2012 12:43
Last Modified:05 Apr 2016 16:05
Publisher:Wiley-Blackwell
ISSN:1059-7794
Publisher DOI:https://doi.org/10.1002/humu.22128
PubMed ID:22644647

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