Alternative titles; symbols
HGNC Approved Gene Symbol: QDPR
SNOMEDCT: 58256000;
Cytogenetic location: 4p15.32 Genomic coordinates (GRCh38): 4:17,486,395-17,512,090 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p15.32 | Hyperphenylalaninemia, BH4-deficient, C | 261630 | Autosomal recessive | 3 |
Dihydropteridine reductase (EC 1.6.99.7) catalyzes the NADH-mediated reduction of quinonoid dihydrobiopterin and is an essential component of the pterin-dependent aromatic amino acid hydroxylating systems (Lockyer et al., 1987).
Dahl et al. (1987) and Lockyer et al. (1987) isolated a cDNA clone for DHPR that spans the complete coding region and presented the nucleotide sequence and predicted amino acid sequence of the protein. They found that the 244-amino acid DHPR protein does not share extensive homology with the enzymatically related protein dihydrofolate reductase (DHFR; 126060).
By study of mouse-human somatic cell hybrids, Kuhl et al. (1979) mapped the structural gene for quinoid dihydropteridine reductase on chromosome 4.
MacDonald et al. (1987) used a portion of a cDNA clone corresponding to the 3-prime end of the human QDPR mRNA as a probe to map that gene by analysis of somatic cell hybrid lines. The regional localization achieved was 4p16.1-p15.1. With the use of a RFLP demonstrated by the probe, they showed only loose linkage of the gene to D4S10, the marker of Huntington disease (143100). Thus, QDPR was excluded as a candidate gene in HD.
Brown and Dahl (1987) reported the localization of the DHPR gene to 4p15.3 by in situ hybridization using a cDNA probe.
On the basis of 2 cases of dihydropteridine reductase deficiency (261630) with overlapping deletions of 4p, Sumi et al. (1990) concluded that the DHPR gene is probably located on 4p15.31.
In a patient with BH4-deficient hyperphenylalaninemia due to dihydropteridine reductase deficiency (HPABH4C; 261630), the offspring of consanguineous parents, Howells et al. (1990) identified homozygosity for a mutation in the QDPR gene (612676.0001).
Smooker and Cotton (1995) reviewed 12 point mutations that had been described in DHPR cDNA, all of which resulted in dihydropteridine reductase deficiency. The mutations resulted in amino acid substitutions, insertions, or premature terminations. A further 2 mutations resulted in aberrant splicing of QDPR transcripts.
Romstad et al. (2000) studied 17 patients belonging to 16 Turkish families with DHPR deficiency. The patients were detected at neonatal screening for hyperphenylalaninemia or upon the development of neurologic symptoms. A mutation screen of the entire open reading frame and all splice sites of the QDPR gene identified 10 different mutations, 7 of which were novel (e.g., 612676.0007). Six of the mutations were missense, 2 were nonsense, and 2 were frameshift mutations. All patients had homoallelic genotypes, which allowed the establishment of genotype-phenotype associations.
Howells et al. (1990) used PCR to amplify the coding sequence of DHPR from the messenger RNA of skin fibroblasts of a Lebanese child with BH4-deficient hyperphenylalaninemia due to DHPR deficiency (HPABH4C; 261630), whose parents were consanguineous. Chemical cleavage of mismatches indicated a mismatched thymine and cytosine at approximately 117 and 147 bases, respectively, from the end of the probe. Cloning and sequencing of the mutant PCR products showed homozygous insertion of the triplet ACT (threonine), after alanine 122 (base 390). Amplification of a small region around this mutation by using genomic DNA as the PCR target indicated that the mutation is completely within an exon. Unequal crossing-over at the second base in the preceding alanine codon and duplication of the bases CTA was suggested as the mechanism of mutagenesis. The cleavage site 147 bases from the end of the probe corresponded to the conversion of guanine to adenine at base 420 (CTG to CTA) and did not alter the code for leucine. This was interpreted to be a common neutral polymorphism because it was seen in another DHPR-deficient child and in a control subject.
By screening the total coding sequence of a cDNA for DHPR by chemical cleavage of mismatch and sequencing of selected portions, Dianzani et al. (1993) identified a gly23-to-asp (G23D) mutation that seemed to be particularly frequent in Mediterranean patients with hyperphenylalaninemia due to dihydropteridine reductase deficiency (261630). Its occurrence within a glycine string common to the amino-terminal region in NADH-dependent enzymes suggested a possible causal mechanism for the defect. See 612676.0006.
In a patient with hyperphenylalaninemia due to dihydropteridine reductase deficiency (261630), Dianzani et al. (1993) identified homozygosity for a trp108-to-gly (W108G) substitution in the QDPR gene. The mutation occurred in a motif that showed similarities with a region of DHFR and conservation within different animal species.
Ikeda et al. (1997) detected a homozygous trp36-to-arg (W36R) mutation of the QDPR gene in a Japanese patient with hyperphenylalaninemia due to DHPR deficiency (261630). The mutation abolished DHPR activity according to an in vitro expression study. The patient was born to first-cousin parents. Although hyperphenylalaninemia was detected in a newborn screening program and she was placed on a low phenylalanine diet from the age of 1 month with good control of serum phenylalanine level, psychomotor development was delayed.
In a Japanese boy with hyperphenylalaninemia due to DHPR deficiency (261630), the offspring of first-cousin parents, Ikeda et al. (1997) found a splicing error mutation. QDPR mRNA was markedly decreased. RT-PCR of the mRNA generated a cDNA fragment with a 152-bp insertion. The inserted sequence contained a termination codon, which probably affected the stability of the mRNA. Analysis of genomic DNA showed that the insertion was derived from the putative intron 3 of the QDPR gene, and an intronic A-to-G substitution was present adjacent to the 3-prime end of the inserted sequence. The nucleotide change generated a sequence similar to an RNA splice donor site and probably activated an upstream cryptic acceptor site, thus producing an abnormal extra exon. Creation of intron-derived pseudoexons as a result of activation of an upstream cryptic acceptor site seems to be a rare type of mutation. The patient had 2 older brothers with hyperphenylalaninemia due to DHPR deficiency Although a low phenylalanine diet was initiated, the patient showed developmental delay and intractable seizures. His IQ was 30 at 11 years of age.
In a patient with hyperphenylalaninemia due to dihydropteridine reductase deficiency (261630), Dianzani et al. (1998) identified a tyr150-to-cys (Y150C) mutation in compound heterozygosity with G23D (612676.0002), a mutation that is always associated with a severe phenotype in homozygous patients. This patient had an intermediate phenotype, with good response to monotherapy with BH4.
In 2 cousins and in a third unrelated patient with hyperphenylalaninemia due to DHPR deficiency (261630), Romstad et al. (2000) identified a 350G-A transition in exon 3 of the QDPR gene causing a trp90-to-ter (W90X) substitution. The peptide chain was predicted to be shortened by 155 amino acids. Although the phenotype was severe, all 3 patients responded well to therapy.
Brown, R. M., Dahl, H.-H. M. Localization of the human dihydropteridine reductase gene to band p15.3 of chromosome 4 by in situ hybridization. Genomics 1: 67-70, 1987. [PubMed: 3666748] [Full Text: https://doi.org/10.1016/0888-7543(87)90106-6]
Dahl, H.-H. M., Hutchison, W., McAdam, W., Wake, S., Morgan, F. J., Cotton, R. G. H. Human dihydropteridine reductase: characterisation of a cDNA clone and its use in analysis of patients with dihydropteridine reductase deficiency. Nucleic Acids Res. 15: 1921-1932, 1987. [PubMed: 3031582] [Full Text: https://doi.org/10.1093/nar/15.5.1921]
Dianzani, I., de Sanctis, L., Smooker, P. M., Gough, T. J., Alliaudi, C., Brusco, A., Spada, M., Blau, N., Dobos, M., Zhang, H.-P., Yang, N., Ponzone, A., Armarego, W. L. F., Cotton, R. G. H. Dihydropteridine reductase deficiency: physical structure of the QDPR gene, identification of two new mutations and genotype-phenotype correlations. Hum. Mutat. 12: 267-273, 1998. [PubMed: 9744478] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1998)12:4<267::AID-HUMU8>3.0.CO;2-C]
Dianzani, I., Howells, D. W., Ponzone, A., Saleeba, J. A., Smooker, P. M., Cotton, R. G. H. Two new mutations in the dihydropteridine reductase gene in patients with tetrahydrobiopterin deficiency. J. Med. Genet. 30: 465-469, 1993. [PubMed: 8326489] [Full Text: https://doi.org/10.1136/jmg.30.6.465]
Howells, D. W., Forrest, S. M., Dahl, H.-H. M., Cotton, R. G. H. Insertion of an extra codon for threonine is a cause of dihydropteridine reductase deficiency. Am. J. Hum. Genet. 47: 279-285, 1990. [PubMed: 2116088]
Ikeda, H., Matsubara, Y., Mikami, H., Kure, S., Owada, M., Gough, T., Smooker, P. M., Dobbs, M., Dahl, H.-H. M., Cotton, R. G. H., Narisawa, K. Molecular analysis of dihydropteridine reductase deficiency: identification of two novel mutations in Japanese patients. Hum. Genet. 100: 637-642, 1997. [PubMed: 9341885] [Full Text: https://doi.org/10.1007/s004390050566]
Kuhl, P., Olek, K., Wardenbach, P., Grzeschik, K.-H. Assignment of a gene for human quinoid-dihydropteridine reductase (QDPR, EC 1.6.5.1) to chromosome 4. Hum. Genet. 53: 47-49, 1979. [PubMed: 295043] [Full Text: https://doi.org/10.1007/BF00289450]
Kuhl, P., Olek, K., Wardenbach, P. Dihydropteridine reductase variation in man and the characid fish 'Cheirodon axelrodi': evidence for a dimeric enzyme structure. Hum. Genet. 55: 99-102, 1980. [PubMed: 7450761] [Full Text: https://doi.org/10.1007/BF00329133]
Lockyer, J., Cook, R. G., Milstien, S., Kaufman, S., Woo, S. L. C., Ledley, F. D. Structure and expression of human dihydropteridine reductase. Proc. Nat. Acad. Sci. 84: 3329-3333, 1987. [PubMed: 3033643] [Full Text: https://doi.org/10.1073/pnas.84.10.3329]
MacDonald, M. E., Anderson, M. A., Lockyer, J. L., Milstien, S., Hobbs, W. J., Faryniarz, A. G., Kaufman, S., Ledley, F. D., Woo, S. L. C., Gusella, J. F. Physical and genetic localization of quinonoid dihydropteridine reductase gene (QDPR) on short arm of chromosome 4. Somat. Cell Molec. Genet. 13: 569-574, 1987. [PubMed: 2889272] [Full Text: https://doi.org/10.1007/BF01534498]
Romstad, A., Kalkanoglu, H. S., Coskun, T., Demirkol, M., Tokatli, A., Dursun, A., Baykal, T., Ozalp, I., Guldberg, P., Guttler, F. Molecular analysis of 16 Turkish families with DHPR deficiency using denaturing gradient gel electrophoresis (DGGE). Hum. Genet. 107: 546-553, 2000. [PubMed: 11153907] [Full Text: https://doi.org/10.1007/s004390000407]
Smooker, P. M., Cotton, R. G. H. Molecular basis of dihydropteridine reductase deficiency. Hum. Mutat. 5: 279-284, 1995. [PubMed: 7627180] [Full Text: https://doi.org/10.1002/humu.1380050402]
Sumi, S., Ishikawa, T., Ito, Y., Oishi, H., Asai, K., Wada, Y. Probable assignment of the dihydropteridine reductase gene to 4p15.31. Tohoku J. Exp. Med. 160: 93-94, 1990. [PubMed: 2330583] [Full Text: https://doi.org/10.1620/tjem.160.93]