DIHYDROPTERIDINE REDUCTASE DEFICIENCY - PHYSICAL STRUCTURE OF THE QDPR GENE, IDENTIFICATION OF 2 NEW MUTATIONS AND GENOTYPE-PHENOTYPE CORRELATIONS

Dihydropteridine reductase (DHPR) is an enzyme involved in recycling o f tetrahydrobiopterin (BH4), the cofactor of the aromatic amino acid h ydroxylases. Its deficiency is characterized by hyperphenylalaninemia due to the secondary defect of phenylalanine hydroxylase and depletion of the neurotransmitters dopamine and serotonin, whose syntheses are controlled by tryptophan and tyrosine hydroxylases. The DHPR cDNA has been cloned and mapped on 4p15.3. In the present study we report the g enomic structure of the DHPR gene (QDPR). This gene includes seven exo ns within a range of 84-564 bp; the corresponding introns are flanked by canonic splice junctions, We also present a panel of PCR primers co mplementary to intronic sequences that greatly facilitates amplificati on of the gene and provides a genomic DNA approach for mutation detect ion. We have used this approach to study six patients with DHPR defici ency, Four known mutations (G23D, H158Y, IVS5G+1A, R221X) and two new mutations (Y150C and G218ins9bp) were found, The Y150C mutation was fo und in compound heterozygosity with G23D, a mutation always associated with a severe phenotype in homozygous patients. This patient has an i ntermediate phenotype (good response to monotherapy with BH4). The mut ant enzyme for Y150C was expressed in an E. coli system. Comparison of its kinetic parameters with those of the G23D mutant enzyme showed th at it is not as effective as the wild type enzyme, but is more active than the G23D mutant. This patient's intermediate phenotype is thus du e to the mild DHPR mutation Y150C, Correlations between genotypes and phenotypes were also found for the other mutations, Hum Mutat 12:267-2 73, 1998, (C) 1998 Wiley-Liss, Inc.