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Published on: October 10, 2022
BH4 responsiveness associated to a PKU mutation with decreased binding affinity for the cofactor
Cristina Aguado1, Belen Pérez, M José García
1Centro de Biología Molecular Severo Ochoa CSIC-UAM, Madrid, Spin.
Summary
Tetrahydrobiopterin (BH4) treatment benefits some phenylketonuria (PKU) patients. A D129G mutation in phenylalanine hydroxylase causes BH4 responsiveness due to decreased BH4 binding affinity.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Phenylketonuria (PKU) is a metabolic disorder.
- Tetrahydrobiopterin (BH4) is a cofactor for phenylalanine hydroxylase.
- BH4 therapy reduces blood phenylalanine in a subset of PKU patients.
Purpose of the Study:
- Investigate the molecular basis of BH4 responsiveness in PKU.
- Analyze the D129G mutation in the phenylalanine hydroxylase gene.
Main Methods:
- BH4 loading test and patient genotyping.
- Expression analysis of the D129G mutation in prokaryotic and eukaryotic systems.
Main Results:
- A patient hemizygous for D129G showed a positive BH4 response.
- Mutant phenylalanine hydroxylase exhibited partial activity and reduced BH4 binding affinity.
- The mutant protein displayed decreased stability in a human hepatoma cell line.
Conclusions:
- The D129G mutation confers a BH4-responsive phenotype in PKU.
- Reduced binding affinity for BH4 is a key characteristic of the D129G mutation.
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