International database of tetrahydrobiopterin deficiencies

Blau, Nenad; Barnes, Isobel; Dhondt, Jean-Louis

doi:10.1007/bf01799342

Cited by 131 publications

(115 citation statements)

References 8 publications

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“…Total RNA was isolated from early and late logarithmic phase promastigotes, metacyclic cells, and lesion amastigotes by using the phenol/guanidine isothyocyanate reagent TRIzol TM (Invitrogen) according to the manufacturer's instructions. Southern and Northern blots were performed following standard procedures (45), and a PCR-derived QDPR hybridization probe (described below) was labeled with [␣- 32 P]dCTP by the random-priming method (46). Quantitation was performed with a laser densitometer (Molecular Dynamics with ImageQuant TM version 3.0; Molecular Dynamics).…”

Section: Methodsmentioning

confidence: 99%

Characterization of quinonoid-Dihydropteridine Reductase (QDPR) from the Lower Eukaryote Leishmania major

Lye

Cunningham

Beverley

2002

Journal of Biological Chemistry

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Biopterin is required for growth of the protozoan parasite Leishmania and is salvaged from the host through the activities of a novel biopterin transporter (BT1) and broad-spectrum pteridine reductase (PTR1). Here we characterize Leishmania major quinonoid-dihydropteridine reductase (LmQDPR), the key enzyme required for regeneration and maintenance of H 4 biopterin pools. LmQDPR shows good homology to metazoan quinonoiddihydropteridine reductase and conservation of domains implicated in catalysis and regulation. Unlike other organisms, LmQDPR is encoded by a tandemly repeated array of 8 -9 copies containing LmQDPR plus two other genes. QDPR mRNA and enzymatic activity were expressed at similar levels throughout the infectious cycle. The pH optima, kinetic properties, and substrate specificity of purified LmQDPR were found to be similar to that of other qDPRs, although it lacked significant activity for non-quinonoid pteridines. These and other data suggest that LmQDPR is unlikely to encode the dihydrobiopterin reductase activity (PTR2) described previously. Similarly LmQDPR is not inhibited by a series of antifolates showing anti-leishmanial activity beyond that attributable to dihydrofolate reductase or PTR1 inhibition. qDPR activity was found in crude lysates of Trypanosoma brucei and Trypanosoma cruzi, further emphasizing the importance of H 4 biopterin throughout this family of human parasites.

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Section: Methodsmentioning

confidence: 99%

Characterization of quinonoid-Dihydropteridine Reductase (QDPR) from the Lower Eukaryote Leishmania major

Lye

Cunningham

Beverley

2002

Journal of Biological Chemistry

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“…3 In contrast to the dietary therapy used for phenylalanine hydroxylase deficiency, the administration of BH4 and neurotransmitters is used for the treatment of most BH4-deficient patients and additional folic acid supplement is recommended for DHPR deficiency. 3, 9 The incidence of BH4 deficiency is B1-3% of HPA patients worldwide, 10 but is more frequent in East Asian, including Taiwan (17%), 4 Mainland China (9%), 11 Thailand (17%), 7 South Korea (10%), the Philippines (23%) and Malaysia (64%) (unpublished data) with the exception of Japan (3%) (unpublished data).…”

Section: Introductionmentioning

confidence: 98%

Mutation spectrum of and founder effects affecting the PTS gene in East Asian populations

Chiu

Chang²,

et al. 2012

J Hum Genet

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The enzyme 6-pyruvoyl-tetrahydropterin synthase (PTPS, gene symbol: PTS) is involved in the second step of the de novo biosynthesis of tetrahydrobiopterin (BH4), which is a vital cofactor of nitric oxide synthases and three types of aromatic amino acid hydroxylases; the latter are important enzymes in the production of neurotransmitters. We conducted a study of PTS mutations in East Asia, including Taiwan, Mainland China, Japan, South Korea, the Philippines, Thailand and Malaysia. A total of 43 mutations were identified, comprising 22 previously reported mutations and 21 new discovered mutations. Among these, the c.155A4G, c.259C4T, c. 272A4G, c.286G4A and c.84-291A4G mutations were the most common PTS mutations in East Asia, while the c.58T4C and c.243G4A mutations were, respectively, specific to Filipinos and Japanese originating from Okinawa. Further studies demonstrated that each of the mutations listed above was in linkage disequilibrium to a specific allele of polymorphic microsatellite marker, D11S1347. These results suggest the presence of founder effects that have affected these frequent mutations in East Asia populations. In this context, D11S1347 should become one of the most reliable polymorphic markers for use in prenatal diagnosis among PTPS deficient families, especially where mutations are yet to be identified.

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“…Individuals with DHPR deficiency may present with hyperphenylalaninemia, microcephaly, hypotonia, mental retardation, and convulsions (Blau et al 1996;Ponzone et al 2004). DHPR deficiency is encoded by the gene QPDR and missense mutations, insertions/deletions, and splice site mutations in the QPDR gene have been associated with DHPR deficiency (Dahl et al 1987;Dianzani et al 1998;Howells et al 1990).…”

Section: Introductionmentioning

confidence: 99%

Dihydropteridine Reductase Deficiency and Treatment with Tetrahydrobiopterin: A Case Report

et al. 2012

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Dihydropteridine reductase (DHPR) deficiency is a genetic disorder of tetrahydrobiopterin (BH4) regeneration and may present with hyperphenylalaninemia, microcephaly, hypotonia, mental retardation, and convulsions. BH4 is an essential cofactor for the hydroxylation of aromatic amino acids and a deficiency of BH4 results in decreased synthesis of dopamine and serotonin. We present a 27-month-old female patient with DHPR deficiency who was treated with L-dopa/carbidopa (2 mg/kg, four times per day), 5-hydroxytryptophan (2 mg/kg, four times per day), folinic acid (10 mg/day), and BH4 supplementation (20 mg/ kg, twice a day). Although remarkable clinical improvement with normal plasma phenylalanine (Phe) levels and increased phenylalanine tolerance was noted 1 month after the treatment, CSF neurotransmitter metabolites did not improve. BH4 supplementation was increased to 40 mg/kg/ day and the CSF study was repeated 1 month later. There was no significant change of CSF neurotransmitters, BH4 or BH2 levels but plasma Phe level was within normal range. Surprisingly, she had developmental improvement noted at 1-month and 3-month visits following an augmented neurotransmitter and BH4 treatment. She was able to pull herself to the standing position and sit down on her own. She was also noted to be more alert and responsive following treatment. Her expressive language did not improve, although her receptive language was markedly improved. The above treatment improved patient's clinical findings, normalized blood Phe levels, and increased Phe tolerance in the diet, but neither 20 nor 40 mg/kg/day BH4 supplementation corrected neurotransmitter or BH4 levels or increased BH2 level in CSF. Further studies are needed to find the optimal management plan for patients with DHPR deficiency.

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International database of tetrahydrobiopterin deficiencies

Cited by 131 publications

References 8 publications

Characterization of quinonoid-Dihydropteridine Reductase (QDPR) from the Lower Eukaryote Leishmania major

Characterization of quinonoid-Dihydropteridine Reductase (QDPR) from the Lower Eukaryote Leishmania major

Mutation spectrum of and founder effects affecting the PTS gene in East Asian populations

Dihydropteridine Reductase Deficiency and Treatment with Tetrahydrobiopterin: A Case Report

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