title: Mapping the functional landscape of frequent phenylalanine hydroxylase (PAH) genotypes promotes personalised medicine in phenylketonuria.
abstract: BACKGROUND
  In phenylketonuria, genetic heterogeneity, frequent compound heterozygosity, and the lack of functional data for phenylalanine hydroxylase genotypes hamper reliable phenotype prediction and individualised treatment.
  
  
  METHODS
  A literature search revealed 690 different phenylalanine hydroxylase genotypes in 3066 phenylketonuria patients from Europe and the Middle East. We determined phenylalanine hydroxylase function of 30 frequent homozygous and compound heterozygous genotypes covering 55% of the study population, generated activity landscapes, and assessed the phenylalanine hydroxylase working range in the metabolic (phenylalanine) and therapeutic (tetrahydrobiopterin) space.
  
  
  RESULTS
  Shared patterns in genotype-specific functional landscapes were linked to biochemical and pharmacological phenotypes, where (1) residual activity below 3.5% was associated with classical phenylketonuria unresponsive to pharmacological treatment; (2) lack of defined peak activity induced loss of response to tetrahydrobiopterin; (3) a higher cofactor need was linked to inconsistent clinical phenotypes and low rates of tetrahydrobiopterin response; and (4) residual activity above 5%, a defined peak of activity, and a normal cofactor need were associated with pharmacologically treatable mild phenotypes. In addition, we provide a web application for retrieving country-specific information on genotypes and genotype-specific phenylalanine hydroxylase function that warrants continuous extension, updates, and research on demand.
  
  
  CONCLUSIONS
  The combination of genotype-specific functional analyses with biochemical, clinical, and therapeutic data of individual patients may serve as a powerful tool to enable phenotype prediction and to establish personalised medicine strategies for dietary regimens and pharmacological treatment in phenylketonuria.
authors.affiliation: Department of Molecular Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Marta K
authors.initials: MK
authors.lastname: Danecka
authors.affiliation: Department of Molecular Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Woidy
authors.affiliation: Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zschocke
authors.affiliation: Department of Pediatrics, Hôpital d'Enfants Brabois, CHU Nancy, Vandoeuvre les Nancy, France.
authors.forename: François
authors.initials: F
authors.lastname: Feillet
authors.affiliation: University Children's Hospital, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Ania C
authors.initials: AC
authors.lastname: Muntau
authors.affiliation: Department of Molecular Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Søren W
authors.initials: SW
authors.lastname: Gersting
mesh_terms: D005060:Europe; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008877:Middle East; D009154:Mutation; D010651:Phenylalanine Hydroxylase / Q000235:genetics*; D010661:Phenylketonurias / Q000235:genetics* / Q000503:physiopathology; D057285:Precision Medicine
chemical_list: D010651:Phenylalanine Hydroxylase
keywords: Activity landscapes; Genotype-phenotype correlation; Personalized medicine; Phenylalanine hydroxylase; Phenylketonuria