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Am J Hum Genet. 2007 Nov;81(5):1006-24. Epub 2007 Oct 2.

Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases.

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Department of Biomedicine, University of Bergen, Bergen, Norway.


Phenylketonuria (PKU) is a genetic disease caused by mutations in human phenylalanine hydroxylase (PAH). Most missense mutations result in misfolding of PAH, increased protein turnover, and a loss of enzymatic function. We studied the prediction of the energetic impact on PAH native-state stability of 318 PKU-associated missense mutations, using the protein-design algorithm FoldX. For the 80 mutations for which expression analyses have been performed in eukaryote systems, in most cases we found substantial overall correlations between the mutational energetic impact and both in vitro residual activities and patient metabolic phenotype. This finding confirmed that the decrease in protein stability is the main molecular pathogenic mechanism in PKU and the determinant for phenotypic outcome. Metabolic phenotypes have been shown to be better predicted than in vitro residual activities, probably because of greater stringency in the phenotyping process. Finally, all the remaining 238 PKU missense mutations compiled at the PAH locus knowledgebase (PAHdb) were analyzed, and their phenotypic outcomes were predicted on the basis of the energetic impact provided by FoldX. Residues in exons 7-9 and in interdomain regions within the subunit appear to play an important structural role and constitute hotspots for destabilization. FoldX analysis will be useful for predicting the phenotype associated with rare or new mutations detected in patients with PKU. However, additional factors must be considered that may contribute to the patient phenotype, such as possible effects on catalysis and interindividual differences in physiological and metabolic processes.

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