title: Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency.
abstract: Mutations in the phenylalanine hydroxylase (PAH) gene result in phenylketonuria (PKU). Tetrahydrobiopterin (BH(4))-responsive hyperphenylalaninemia has been recently described as a variant of PAH deficiency caused by specific mutations in the PAH gene. It has been suggested that BH(4)-responsiveness may be predicted from the corresponding genotypes. Data from BH(4) loading tests indicated an incidence of BH(4)-responsiveness of >40% in the general PKU population and >80% in mild PKU patients. The current project entailed genotype analysis of 315 BH(4)-responsive patients tabulated in the BIOPKUdb database and comparison with the data from the PAHdb locus-specific knowledgebase, as well as with previously published PAH mutations for several European countries, Northern China, and South Korea. We identified 57 mutations, presenting with a substantial residual PAH activity (average approximately 47%), presumed to be associated with BH(4)-responsiveness. More than 89% of patients are found to be compound heterozygotes. The three most common mutations found in >5% of BH(4)-responsive patients are p.A403 V, p.R261Q, and p.Y414C. Using the Hardy-Weinberg formula the predicted average frequency of BH(4)-responsiveness in European populations was calculated to be 55% (range 17-79%, lowest in Baltic countries and Poland and highest in Spain), 57% in Northern China, and 55% for South Korea. The genotype-predicted prevalence of BH(4)-responsiveness was higher than prevalence data obtained from BH(4) loading tests. Inconsistent results were observed for mutations p.L48S, p.I65 T, p.R158Q, p.R261Q, and p.Y414C. Our data suggest that BH(4)-responsiveness may be more common than assumed and to some extent may be predicted or excluded from the patient's genotype.
authors.affiliation: Division of Clinical Chemistry and Biochemistry, University Children's Hospital, Zürich, Switzerland.
authors.forename: Marcel R
authors.initials: MR
authors.lastname: Zurflüh
authors.forename: Johannes
authors.initials: J
authors.lastname: Zschocke
authors.forename: Martin
authors.initials: M
authors.lastname: Lindner
authors.forename: François
authors.initials: F
authors.lastname: Feillet
authors.forename: Céline
authors.initials: C
authors.lastname: Chery
authors.forename: Alberto
authors.initials: A
authors.lastname: Burlina
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.forename: Beat
authors.initials: B
authors.lastname: Thöny
authors.forename: Nenad
authors.initials: N
authors.lastname: Blau
mesh_terms: D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D002681:China; D005060:Europe; D015971:Gene Expression Regulation, Enzymologic; D005787:Gene Frequency; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D007723:Korea; D008958:Models, Molecular; D009154:Mutation; D010651:Phenylalanine Hydroxylase / Q000172:deficiency* / Q000235:genetics*; D010661:Phenylketonurias / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism
chemical_list: D001708:Biopterins; D010651:Phenylalanine Hydroxylase; C003402:sapropterin