TY - JOUR
T1 - Dihydropteridine reductase deficiency
T2 - Physical structure the QDPR gene, identification two new mutations and genotype-phenotype correlations
AU - Dianzani, Irma
AU - De Sanctis, Luisa
AU - Smooker, Peter M.
AU - Gough, Tamara J.
AU - Alliaudi, Caria
AU - Brusco, Alfredo
AU - Spada, Marco
AU - Blau, Nenad
AU - Dobos, Marion
AU - Zhang, Hong Ping
AU - Yang, Nan
AU - Ponzone, Alberto
AU - Armarego, Wilfred L F
AU - Cotton, Richard G H
PY - 1998
Y1 - 1998
N2 - Dihydropteridine reductase (DHPR) is an enzyme involved in recycling of tetrahydrobiopterin (BH4), the cofactor of the aromatic amino acid hydroxylases. 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 genomic structure of the DHPR gene (QDPR). This gene includes seven exons within a range of 84-564 bp; the corresponding introns are flanked by canonic splice junctions. We also present a panel of PCR primers complementary to intronic sequences that greatly facilitates amplification of the gene and provides a genomic DNA approach for mutation detection. We have used this approach to study six patients with DHPR deficiency. Four known mutations (G23D, H158Y, IVS5G+ 1A, R221x) and two new mutations (Y150C and G2181ns9bp) were found. The Y150C mutation was found in compound heterozygosity with G23D, a mutation always associated with a severe phenotype in homozygous patients. This patient has an intermediate phenotype (good response to monotherapy with BH4). The mutant enzyme for Y150C was expressed in an E. coli system. Comparison of its kinetic parameters with those of the G23D mutant enzyme showed that 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 due to the mild DHPR mutation Y150C. Correlations between genotypes and phenotypes were also found for the other mutations.
AB - Dihydropteridine reductase (DHPR) is an enzyme involved in recycling of tetrahydrobiopterin (BH4), the cofactor of the aromatic amino acid hydroxylases. 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 genomic structure of the DHPR gene (QDPR). This gene includes seven exons within a range of 84-564 bp; the corresponding introns are flanked by canonic splice junctions. We also present a panel of PCR primers complementary to intronic sequences that greatly facilitates amplification of the gene and provides a genomic DNA approach for mutation detection. We have used this approach to study six patients with DHPR deficiency. Four known mutations (G23D, H158Y, IVS5G+ 1A, R221x) and two new mutations (Y150C and G2181ns9bp) were found. The Y150C mutation was found in compound heterozygosity with G23D, a mutation always associated with a severe phenotype in homozygous patients. This patient has an intermediate phenotype (good response to monotherapy with BH4). The mutant enzyme for Y150C was expressed in an E. coli system. Comparison of its kinetic parameters with those of the G23D mutant enzyme showed that 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 due to the mild DHPR mutation Y150C. Correlations between genotypes and phenotypes were also found for the other mutations.
KW - Dihydropteridine reductase
KW - Genotype/phenotype correlation
KW - Hyperphenylalaninemia
KW - Tetrahydrobiopterin deficiency
UR - http://www.scopus.com/inward/record.url?scp=7344244334&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=7344244334&partnerID=8YFLogxK
U2 - 10.1002/(SICI)1098-1004(1998)12:4<267::AID-HUMU8>3.0.CO;2-C
DO - 10.1002/(SICI)1098-1004(1998)12:4<267::AID-HUMU8>3.0.CO;2-C
M3 - Article
C2 - 9744478
AN - SCOPUS:7344244334
VL - 12
SP - 267
EP - 273
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
IS - 4
ER -