Title | Linking genotypes database with locus-specific database and genotype-phenotype correlation in phenylketonuria. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Wettstein S, Underhaug J, Perez B, Marsden BD, Yue WW, Martinez A, Blau N |
Journal | Eur J Hum Genet |
Volume | 23 |
Issue | 3 |
Pagination | 302-9 |
Date Published | 2015 Mar |
ISSN | 1476-5438 |
Keywords | Alleles, Databases, Genetic, Female, Gene Frequency, Genetic Association Studies, Genotype, Humans, Male, Mutation, Phenotype, Phenylketonurias |
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. |
DOI | 10.1038/ejhg.2014.114 |
Alternate Journal | Eur. J. Hum. Genet. |
PubMed ID | 24939588 |
PubMed Central ID | PMC4326710 |
Grant List | 092809 / / Wellcome Trust / United Kingdom |