Molecular genetics of tetrahydrobiopterin‐responsive phenylalanine hydroxylase deficiency

  title={Molecular genetics of tetrahydrobiopterin‐responsive phenylalanine hydroxylase deficiency},
  author={Marcel R. Zurfl{\"u}h and Johannes Zschocke and Martin Lindner and François Feillet and C{\'e}line Ch{\'e}ry and Alberto B Burlina and Raymond C. Stevens and Beat Th{\"o}ny and Nenad Blau},
  journal={Human Mutation},
Mutations in the phenylalanine hydroxylase (PAH) gene result in phenylketonuria (PKU. [] Key Method 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…

Significance of genotype in tetrahydrobiopterin-responsive phenylketonuria

These results show that BH4 non-responsiveness is associated with genotype, however, patients with mutations in the regulatory domain show inconsistent results.

Genetics of Phenylketonuria: Then and Now

A greater understanding of the relationships between individual gene variant, residual PAH activity, tetrahydrobiopterin (BH4) responsiveness, and the clinical PKU phenotype may increase the potential for individualized management of PKU in future.

Functional Characterization of Novel Phenylalanine Hydroxylase p.Gln226Lys Mutation Revealed Its Non-responsiveness to Tetrahydrobiopterin Treatment in Hepatoma Cellular Model

Treatment with tetrahydrobiopterin (BH4) is the latest therapeutic option approved for patients with phenylketonuria (PKU)—one of the most frequent inborn metabolic diseases. PKU or phenylalanine

Mutational spectrum of phenylketonuria in Jiangsu province

The first report on the spectrum of PAH variants in Jiangsu province is presented, which identifies one novel PAH variant and tries to show a genotype–phenotype relationship also regarding BH4-responsiveness.

Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness.

The proportion of phenylketonuria-patients who could benefit from the use of BH4 reaches approximately 10% in the entire region, which is similar percentage of the "BH4-responsive" variants of a PAH gene in patients from other countries of Eastern Europe.

Unresponsiveness to tetrahydrobiopterin of phenylalanine hydroxylase deficiency.

Correlation between genotype and the tetrahydrobiopterin-responsive phenotype in Chinese patients with phenylketonuria

Genotype-based predictions of BH4-responsiveness are only for selecting potential responders and it is necessary to test potential responders with a long-term BH 4 challenge.

Molecular mechanisms of PAH function in response to phenylalanine and tetrahydrobiopterin binding

Detailed knowledge on the mechanism of the misfolding-induced loss of function in PAH deficiency enabled a better understanding of the molecular mode of action of pharmacological rescue of enzyme function by BH4.

Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness

This study is the first of its kind, in a French population, to identify the phenotype associated with several combinations of PAH mutations, and highlights the necessity of performing simultaneously BH4 loading test and molecular analysis in monitoring phenylketonuria patients.



A hypothesis on the biochemical mechanism of BH4-responsiveness in phenylalanine hydroxylase deficiency

The results indicate that oral BH4 supplementation may be used as long-term treatment for individuals with BH 4-responsive PAH deficiency, either without or in combination with a less restrictive diet.

A structural hypothesis for BH4 responsiveness in patients with mild forms of hyperphenylalaninaemia and phenylketonuria

It is proposed that other subsets of PAH mutations will have a high likelihood of being responsive to oral BH4 administration, and it is believed that some of these mutations result in expressed mutant enzymes that are Km variants (with a lower binding affinity for BH 4) of the standard PAH enzyme phenotype.

Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: a metanalysis of genotype-phenotype correlations.

The majority of PAH mutations confer a consistent phenotype and that this is concordant with their effects, when known, predicted from in vitro expression analysis, however, significant inconsistencies reveal that the HPA-phenotype is more complex than that predicted by Mendelian inheritance of alleles at the PAH locus.

Incidence of BH4-responsiveness in phenylalanine-hydroxylase-deficient Italian patients.

Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria.

Tetrahydrobiopterin responsiveness is common in patients with mild hyperphenylalaninemia phenotypes and cannot consistently be predicted on the basis of genotype, particularly in compound heterozygotes.

Tetrahydrobiopterin responsiveness: results of the BH4 loading test in 31 Spanish PKU patients and correlation with their genotype.