title: Linking genotypes database with locus-specific database and genotype-phenotype correlation in phenylketonuria.
abstract: The wide range of metabolic phenotypes in phenylketonuria is due to a large number of variants causing variable impairment in phenylalanine hydroxylase function. A total of 834 phenylalanine hydroxylase gene variants from the locus-specific database PAHvdb and genotypes of 4181 phenylketonuria patients from the BIOPKU database were characterized using FoldX, SIFT Blink, Polyphen-2 and SNPs3D algorithms. Obtained data was correlated with residual enzyme activity, patients' phenotype and tetrahydrobiopterin responsiveness. A descriptive analysis of both databases was compiled and an interactive viewer in PAHvdb database was implemented for structure visualization of missense variants. We found a quantitative relationship between phenylalanine hydroxylase protein stability and enzyme activity (r(s) = 0.479), between protein stability and allelic phenotype (r(s) = -0.458), as well as between enzyme activity and allelic phenotype (r(s) = 0.799). Enzyme stability algorithms (FoldX and SNPs3D), allelic phenotype and enzyme activity were most powerful to predict patients' phenotype and tetrahydrobiopterin response. Phenotype prediction was most accurate in deleterious genotypes (≈ 100%), followed by homozygous (92.9%), hemizygous (94.8%), and compound heterozygous genotypes (77.9%), while tetrahydrobiopterin response was correctly predicted in 71.0% of all cases. To our knowledge this is the largest study using algorithms for the prediction of patients' phenotype and tetrahydrobiopterin responsiveness in phenylketonuria patients, using data from the locus-specific and genotypes database.
authors.affiliation: Division of Metabolism, University Children's Hospital, Zürich, Switzerland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wettstein
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Jarl
authors.initials: J
authors.lastname: Underhaug
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biologia Molecular UAM-CSIC, CIBERER, IDIPAZ Universidad Autonoma de Madrid, Madrid, Spain.
authors.forename: Belen
authors.initials: B
authors.lastname: Perez
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford, UK.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Marsden
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford, UK.
authors.forename: Wyatt W
authors.initials: WW
authors.lastname: Yue
authors.affiliation: Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Aurora
authors.initials: A
authors.lastname: Martinez
authors.affiliation: 1] Division of Metabolism, University Children's Hospital, Zürich, Switzerland [2] Division of Inborn Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
authors.forename: Nenad
authors.initials: N
authors.lastname: Blau
mesh_terms: D000483:Alleles; D030541:Databases, Genetic; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D010661:Phenylketonurias / Q000175:diagnosis* / Q000235:genetics*