Phenylketonuria (PKU) is a disease caused by mutations in the gene for phenylalanine hydroxylase (PAH) that is inherited as an autosomal recessive and is the most common genetic disorder of amino acid metabolism. This disease has a high genetic diversity with over 500 described mutations associated with disease. The classic way to establish a correlation between genotype and phenotype in patients has been the development of genetic and clinical studies using a large number of patients homozygous or hemizygous functional. However, given the genetic heterogeneity, many patients can not be included in this analysis, the rarity of the mutations they carry, or the wearing of two different mutations nonzero. The in vitro expression of more than a hundred of these mutations indicates that the main mechanism responsible for the disease is the destabilization of the protein and defects in intracellular folding.


Spanish researchers from the Department of Biomedicine, University of Bergen (Norway) and the Centre for Genomic Regulation in Barcelona have collaborated to analyze the impact energy of 318 amino acid change mutations in the PAH protein using the algorithm FoldX and crystal structures available for truncated forms of the protein in rat and human. The tests have allowed to dissect the effect of mutations: effects on the environment of the mutated residue (parameter y0) and the effect of Van der Waals collisions with debris coming (parameter m) that may lead to reorganization of the structure protein.


The fact that a correlation is observed between the phenotypes and associated energy penalties, allowed to set values of these parameters for the different phenotypes and use in the prediction of phenotypes associated with 238 other rare mutations, through a novel method . The method can be applied to other protein-folding diseases associated with mutations of amino acid change.