Disease relevance of QDPR

• Phenylketonuria due to a deficiency of dihydropteridine reductase [1].
• The crystallographic structure of a human dihydropteridine reductase NADH binary complex expressed in Escherichia coli by a cDNA constructed from its rat homologue [2].
• The cofactor product of the aromatic amino acid hydroxylases, 4a-hydroxy-6(R)-tetrahydrobiopterin, requires dehydration before tetrahydrobiopterin can be regenerated by dihydropteridine reductase [3].
• The pathomechanism of familial hypokalemic periodic paralysis (HypoPP) is a mystery, despite knowledge of the underlying dominant point mutations in the dihydropyridine receptor (DHPR) voltage sensor [4].
• In five HypoPP families without DHPR gene defects, we identified two mutations, Arg-672-->His and -->Gly, in the voltage sensor of domain 2 of a different protein: the skeletal muscle sodium channel alpha subunit, known to be responsible for hereditary muscle diseases associated with myotonia [4].

Psychiatry related information on QDPR

• 1. This physical localization places QDPR in the same area of the genome that contains the defect causing Huntington's disease (HD) [5].
• Although there was no relation between baseline psychomotor function and either indices of cumulative aluminium exposure or erythrocyte DHPR activity, changes in DHPR induced by desferrioxamine correlated with changes in psychomotor performance (r = 0.62) [6].
• Brains from subjects with senile dementia of Alzheimer type retain their ability to synthesis neopterin and have normal dihydropteridine reductase activity, indicating a specific loss of ability to convert dihydroneopterin triphosphate to tetrahydrobiopterin [7].
• At age 6 years his mental retardation and neurologic impairment are less severe than reported in most patients with DHPR deficiency [8].

High impact information on QDPR

• The enzyme dihydropteridine reductase (DHPR) is essential for the maintenance of normal brain concentrations of tetrahydrobiopterin, which is itself required for the synthesis of specific neurotransmitters [9].
• These studies suggest that aluminum inhibits DHPR activity in erythrocytes and that aluminum chelation reverses this effect [9].
• We measured erythrocyte DHPR activity and concentrations of the biopterin derivatives of its substrate and of aluminum in 38 patients on hemodialysis who had no clinical evidence of encephalopathy [9].
• Eighteen patients were given the aluminum-chelating agent deferoxamine in a single dose, after which DHPR activity doubled [9].
• Atypical phenylketonuria with normal dihydropteridine reductase activity [10].

Chemical compound and disease context of QDPR

• The new combined loading test was performed in nine patients with primary HPA, three with classical phenylketonuria (PKU), three with DHPR deficiency, and three with 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency [11].
• Phenylalanine has no effect on dihydropteridine reductase activity in phenylketonuria fibroblasts [12].
• A patient with atypical phenylketonuria and normal liver dihydropteridine reductase and phenylalanine-4-hydroxylase activities excreted neopterin but not biopterin or dihydrobiopterin in urine [13].
• Plasma and CSF concentrations of endogenous L-DOPA, catecholamines, and metabolites of monoamines were assayed in a patient with atypical phenylketonuria due to absent dihydropteridine reductase (DHPR), before and during treatment with folinic acid, Sinemet, and 5-hydroxytryptophan [14].
• Methotrexate inhibits DPR activity in vitro with an I50 of approximately 20 microM, but has no effect on the rate of DOPA formation in intact pheochromocytoma cells [15].

Biological context of QDPR

• To identify the disease causing molecular defects, we developed a sensitive screening method that rapidly scans the entire open reading frame and all splice sites of the QDPR gene [16].
• Linkage analyses using recombinant inbred strains, a standard outcross, and an interspecific backcross were used to assign homologs for five human loci, D4S43, D4S62, QDPR, D4S76, and D4S80, to chromosome 5 and to determine their relationships with previously mapped markers for this autosome [17].
• This observation supports the assignment of a structural gene for QDPR to human chromosome 4 [18].
• The method is useful for rapid and simultaneous scanning of all exons and flanking intronic sequences of the QDPR gene [19].
• The QDPR probe revealed a restriction fragment length polymorphism with the enzyme BanII, permitting determination of its genetic proximity to D4S10, an anonymous DNA marker tightly linked to HD [5].

Anatomical context of QDPR

• We examined 8 patients with DRD, 3 with autosomal recessive GTPCH deficiency, 7 with PTPS deficiency, 3 with DHPR deficiency, and 49 controls (35 fibroblast and 14 amniocyte samples) [20].
• A portion of a cDNA clone corresponding to the 3' end of the human quinonoid dihydropteridine reductase (QDPR) mRNA was used as a probe to physically map the QDPR gene by analysis of somatic cell hybrid lines [5].
• Gene transfer of the recombinant human DHPR into COS cells leads to expression of DHPR enzymatic activity [21].
• Inhibition of dihydropteridine reductase from human liver and rat striatal synaptosomes by apomorphine and its analogs [22].
• These results support the concept that the same structural gene(s) encodes for dihydropteridine reductase in human liver, fibroblasts and lymphocytes [23].

Associations of QDPR with chemical compounds

• PTPS- and DHPR-deficient cells showed no enzyme activities; in PTPS deficiency the pattern of pterin production was typical (neopterin, 334-734 pmol/mg; controls, 18-98 pmol/mg; biopterin, 0 pmol/mg; controls, 154-303 pmol/mg) [20].
• Treatment of BH4 deficiencies consists of BH4 supplementation (2-20 mg/kg per day) or diet to control blood phenylalanine concentration and replacement therapy with neurotransmitters precausers (L-dopa/CarbiDOPA and 5-hydroxytryptophan), and supplements of folinic acid in DHPR deficiency [24].
• BH4 deficiency has been diagnosed in patients with hyperphenylalaninemia (HPA) by neonatal mass-screening based on BH4 oral loading tests, analysis of urinary or serum pteridines, and measurement of dihydropterindine reductase (DHPR) activity in blood from a Guthrie card [24].
• Since dihydropteridine reductase is also essential for the biosynthesis of dopamine, norepinephrine, and serotonin, disturbed neurotransmitter function may be responsible for the patient's neurologic deterioration [1].
• Dihydropteridine reductase (DHPR; 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 [21].

Other interactions of QDPR

• We have also used this technique to demonstrate homomeric interactions between wild-type DHPR subunits and between wild-type PCD subunits [25].
• Mutations in the BH4-metabolizing genes GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase, sepiapterin reductase, carbinolamine-4a-dehydratase, and dihydropteridine reductase [26].
• Linkage analysis between the D4S18, D4S23, and QDPR loci and Treacher Collins syndrome in eight families excluded the Treacher Collins syndrome locus from the region of the deletion [27].
• QDPR is only loosely linked to D4S10, excluding any primary role for the gene in HD [5].
• The hDHPR protein does not share extensive homology with the enzymatically related protein human dihydrofolate reductase [28].

Analytical, diagnostic and therapeutic context of QDPR

• Our findings suggest that DGGE is a fast and efficient method for detection of mutations in the QDPR gene, which may be useful for confirmatory DNA-based diagnosis, genetic counselling and prenatal diagnosis in DHPR deficiency [16].
• This method combines PCR amplification and "GC-clamping" of each of the seven exonic regions of QDPR, resolution of mutations by denaturing gradient gel electrophoresis (DGGE), and identification of mutations by direct sequence analysis [16].
• Serum aluminum levels and erythrocyte dihydropteridine reductase activity in patients on hemodialysis [9].
• Three of these are located at different intron/exon boundaries within the DHPR gene, and disrupt the maturation of the DHPR transcript such that little full-length mRNA can be detected by RT-PCR [29].
• Localization of the human dihydropteridine reductase gene to band p15.3 of chromosome 4 by in situ hybridization [30].

References