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S Y Takahashi - One of the best experts on this subject based on the ideXlab platform.
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Phosphorylation by Ca2+/calmodulin-dependent protein kinase II and protein kinase C of Sepiapterin Reductase, the terminal enzyme in the biosynthetic pathway of tetrahydrobiopterin.
FEBS letters, 1994Co-Authors: S Katoh, Tsutomu Sueoka, Y Yamamoto, S Y TakahashiAbstract:Sepiapterin Reductase, the terminal enzyme in the biosynthetic pathway of tetrahydrobiopterin, was stoichiometrically phosphorylated by Ca2+/calmodulin-dependent protein kinase II and protein kinase C (Ca2+/phospholipid-dependent protein kinase) in vitro. Maximal incorporation of phosphate into the enzyme subunit by these was 3.05 +/- 0.05 (n = 4) and 0.74 +/- 0.03 (n = 5) 32P mol per mol enzyme subunit, respectively. The enzyme was not phosphorylated by cyclic nucleotide-dependent protein kinase of either the cAMP-dependent or cGMP-dependent type in this study. Dihydropteridine Reductase, another enzyme working in direct supply of tetrahydrobiopterin, was also a good substrate for Ca2+/calmodulin-dependent protein kinase II. Phosphorylation of Sepiapterin Reductase by these protein kinases modified the kinetic properties of the enzyme. It is likely that these multifunctional Ca(2+)-activated protein kinases may play a role in the regulation of the physiological function of the BH4-generating enzymes in vivo, as was previously found in the case of BH4-requiring enzymes.
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phosphorylation by ca2 calmodulin dependent protein kinase ii and protein kinase c of Sepiapterin Reductase the terminal enzyme in the biosynthetic pathway of tetrahydrobiopterin
FEBS Letters, 1994Co-Authors: S Katoh, Y Yamamoto, Terumi Sueoka, S Y TakahashiAbstract:Sepiapterin Reductase, the terminal enzyme in the biosynthetic pathway of tetrahydrobiopterin, was stoichiometrically phosphorylated by Ca2+/calmodulin-dependent protein kinase II and protein kinase C (Ca2+/phospholipid-dependent protein kinase) in vitro. Maximal incorporation of phosphate into the enzyme subunit by these was 3.05 ± 0.05 (n = 4) and 0.74 ± 0.03 (n = 5) 32P mol per mol enzyme subunit, respectively. The enzyme was not phosphorylated by cyclic nucleotide-dependent protein kinase of either the cAMP-dependent or cGMP-dependent type in this study. Dihydropteridine Reductase, another enzyme working in direct supply of tetrahydrobiopterin, was also a good substrate for Ca2+/calmodulin-dependent protein kinase II. Phosphorylation of Sepiapterin Reductase by these protein kinases modified the kinetic properties of the enzyme. It is likely that these multifunctional Ca2+-activated protein kinases may play a role in the regulation of the physiological function of the BH4-generating enzymes in vivo, as was previously found in the case of BH4-requiring enzymes.
Nenad Blau - One of the best experts on this subject based on the ideXlab platform.
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dopamine responsive growth hormone deficiency and central hypothyroidism in Sepiapterin Reductase deficiency
JIMD reports, 2015Co-Authors: Matthias Zielonka, Nenad Blau, Nawal Makhseed, Markus Bettendorf, Georg F Hoffmann, Thomas OpladenAbstract:Sepiapterin Reductase (SR) deficiency is a rare autosomal recessively inherited error of tetrahydrobiopterin (BH4) biosynthesis, resulting in disturbed dopaminergic and serotonergic neurotransmission. The clinical phenotype is characterized by dopa-responsive movement disorders including muscular hypotonia, dystonia, and parkinsonism. Due to the rarity of the disease, the phenotype of SR deficiency is far from being completely understood. Here, we report a 7-year-old boy, who was referred for diagnostic evaluation of combined psychomotor retardation, spastic tetraplegia, extrapyramidal symptoms, and short stature. Due to discrepancy between motor status and mental condition, analyses of biogenic amines and pterins in CSF were performed, leading to the diagnosis of SR deficiency. The diagnosis was confirmed by a novel homozygous mutation c.530G>C; p.(Arg177Pro) in exon 2 of the SPR gene. Because of persistent short stature, systematic endocrinological investigations were initiated. Insufficient growth-hormone release in a severe hypoglycemic episode after overnight fasting confirmed growth-hormone deficiency as a cause of short stature. In addition, central hypothyroidism was present. A general hypothalamic affection could be excluded. Since dopamine is known to regulate growth-hormone excretion, IGF-1, IGF-BP3, and peripheral thyroid hormone levels were monitored under l-dopa/carbidopa supplementation. Both growth-hormone-dependent factors and thyroid function normalized under treatment. This is the first report describing growth-hormone deficiency and central hypothyroidism in SR deficiency. It extends the phenotypic spectrum of the disease and identifies dopamine depletion as cause for the endocrinological disturbances.
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Clinical and genetic studies in a family with a novel mutation in the Sepiapterin Reductase gene.
Acta neurologica Scandinavica. Supplementum, 2014Co-Authors: Jeanette Koht, Nenad Blau, Thomas Opladen, Aina Rengmark, Kari Anne Bjørnarå, T. Selberg, Chantal M E Tallaksen, Mathias ToftAbstract:OBJECTIVES: Sepiapterin Reductase deficiency is a rare, but treatable inherited disorder of tetrahydrobiopterin and neurotransmitter metabolism. This disorder is most probably underdiagnosed. To date, only 44 cases have been described in the literature. We present the clinical and genetic investigations in a family with a complex movement disorder. MATERIALS AND METHODS: We examined two affected sisters and three healthy family members. The cerebrospinal fluid was analyzed for neurotransmitter and pterins, and the Sepiapterin Reductase gene (SPR) was sequenced. RESULTS: The sisters had a complex movement disorders with dystonia and diurnal fluctuations. Both had oculogyric crises, and the older sister also hypersomnia. Both sisters had raised prolactin levels twice above the reference level. One sister had a dramatic response to levodopa, the other responded, but developed dyskinesia despite low doses. Both patients improved dramatically over time with levodopa (2.3 and 1.5 mg/kg/day). Very low levels of homovanillic acid and 5-hydroxyindoleacetic acid and increased levels of Sepiapterin and dihydrobiopterin were measured in the cerebrospinal fluid before treatment. DNA analyses revealed a novel homozygous mutation in exon 2 in the SPR gene, c.364A>G/p.(Tyr123Cys), located in a highly conserved region in the gene. Both parents and the healthy sister were carriers for the same mutation. CONCLUSIONS: A new homozygous mutation in the SPR gene was found in two sisters with dopa-responsive dystonia. This important and treatable neurotransmitter disorder must be considered in patients with a complex movement disorder with diurnal fluctuations with or without intellectual impairment. Patients with these symptoms should undergo levodopa trial, cerebrospinal fluid investigations, and genetic analyses.
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Clinical Chemistry 47:3 477–485 (2001) Molecular Diagnostics and Genetics Diagnosis of Dopa-responsive Dystonia and Other Tetrahydrobiopterin Disorders by the Study of Biopterin Metabolism in Fibroblasts
2013Co-Authors: Luisa Bonafé, Beat Thöny, Walter Leimbacher, Lucja Kierat, Nenad BlauAbstract:(BH 4) defects are inherited disorders characterized by monoamine neurotransmitter deficiency with decreased activity of one of the BH 4-metabolizing enzymes. The aim of the study was to determine the utility of cultured skin fibroblasts for the diagnosis of these diseases. Methods: Neopterin and biopterin production and GTP cyclohydrolase I (GTPCH) activity were measured in cytokine-stimulated fibroblasts; 6-pyruvoyltetrahydropterin synthase (PTPS), Sepiapterin Reductase (SR), and dihydropteridine Reductase (DHPR) activities were measured in unstimulated fibroblasts. 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 amniocyt
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child neurology paroxysmal stiffening upward gaze and hypotonia hallmarks of Sepiapterin Reductase deficiency
Neurology, 2012Co-Authors: Patricia Dill, Beat Thöny, Nenad Blau, Michael Wagner, A Somerville, Peter WeberAbstract:Sepiapterin Reductase deficiency (SRD) is a dopa-sensitive neurotransmitter disorder, caused by mutation of the SPR gene located on chromosome 2p14-p12.1 To date, 31 patients with 14 mutations have been diagnosed (BIODEF database, update November 2010, www.biopku.org). While classic tetrahydrobiopterin deficiencies present with hyperphenylalaninemia and deficiency of monoamine neurotransmitters, SRD is typically associated with normal phenylalanine levels in blood and pterins in urine2 and not detectable by neonatal screening for phenylketonuria. This implies how important it is to diagnose this condition clinically, in order to provide timely and proper treatment. A summary of the pathophysiology and biochemical pathway is provided by Bonafe et al.2 With the following case report and review of 21 published cases,2,–,10 we elucidate the clinical features of SRD as well as the diagnostic strategy and therapeutic approach. We present a 5-month-old girl, the first and only child born to consanguineous Turkish parents. The parents described the girl's abnormal movements at 3 months of age as sudden stiffening of the whole body, extension of the extremities, upward gaze, and chewing movements lasting for several minutes often after meals, which we also could observe during her hospital stay. Pregnancy and delivery were uneventful. Birthweight, length, and head circumference were within normal ranges. During EEG, a few episodes with chewing movements could be recorded, but no epileptic discharges were evident. The brain MRI was unremarkable. We suspected gastroesophageal reflux and started therapy with omeprazole. The parents reported that the episodes diminished. At 8 months of age, the patient was readmitted because the crises recurred with an increased frequency and duration of up to 25 minutes. During the episodes, the patient revealed circling movements of the hands and rhythmic tremor of the tongue in addition to the previously mentioned symptoms. Remarkably, the …
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Two Greek siblings with Sepiapterin Reductase deficiency
Molecular genetics and metabolism, 2008Co-Authors: Marcel M. Verbeek, Nico G Abeling, Beat Thöny, Nenad Blau, Michèl A.a.p. Willemsen, Ron A. Wevers, Aart J. Lagerwerf, Euthymia Vargiami, Dimitrios I. ZafeiriouAbstract:BACKGROUND: Sepiapterin Reductase (SR) deficiency is a rare inherited disorder of neurotransmitter metabolism; less than 25 cases have been described in the literature so far. METHODS: We describe the clinical history and extensive cerebrospinal fluid (CSF) and urine examination of two Greek siblings with the diagnosis of SR deficiency. The diagnosis was confirmed by enzyme activity measurement in cultured fibroblasts and by mutation analysis. RESULTS: Both patients suffered from a progressive and complex L-dopa responsive movement disorder. Very low concentrations of the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) were observed in CSF. CSF neopterin and biopterin concentrations were abnormal in one case only, whereas in both cases Sepiapterin concentrations were abnormally high and 5-hydroxytryptophan was undetectable. Urine concentrations of HVA, 5-HIAA and vanillyl mandelic acid (VMA) were decreased in both cases. Both patients had no detectable SR enzyme activity in primary dermal fibroblasts, and upon analysis of genomic DNA revealed the same homozygous point mutation introducing a premature stop codon into the reading frame of the SPR gene (mutant allele K251X). CONCLUSIONS: Our cases illustrate that, apart from HVA and 5-HIAA analysis, the specific quantification of Sepiapterin in CSF, rather than neopterin and biopterin alone, is crucial to the final diagnosis of SR deficiency. In addition, urinary concentrations of neurotransmitter metabolites may be abnormal in SR deficiency and may provide an initial indication of SR deficiency before CSF analysis is performed. The known, impressive beneficial response of SR deficient patients to treatment with L-dopa, is illustrated again in our cases.
Andre S Bachmann - One of the best experts on this subject based on the ideXlab platform.
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effect of sulfasalazine on human neuroblastoma analysis of Sepiapterin Reductase spr as a new therapeutic target
BMC Cancer, 2015Co-Authors: Dirk Geerts, Gabor Mocz, Jan Koster, Andre S Bachmann, Lisette P YcoAbstract:Neuroblastoma (NB) is an aggressive childhood malignancy in children up to 5 years of age. High-stage tumors frequently relapse even after aggressive multimodal treatment, and then show therapy resistance, typically resulting in patient death. New molecular-targeted compounds that effectively suppress tumor growth and prevent relapse with more efficacy are urgently needed. We and others previously showed that polyamines (PA) like spermidine and spermine are essential for NB tumorigenesis and that DFMO, an inhibitor of the key PA synthesis gene product ODC, is effective both in vitro and in vivo, securing its evaluation in NB clinical trials. To find additional compounds interfering with PA biosynthesis, we tested sulfasalazine (SSZ), an FDA-approved salicylate-based anti-inflammatory and immune-modulatory drug, recently identified to inhibit Sepiapterin Reductase (SPR). We earlier presented evidence for a physical interaction between ODC and SPR and we showed that RNAi-mediated knockdown of SPR expression significantly reduced native ODC enzyme activity and impeded NB cell proliferation. Human NB mRNA expression datasets in the public domain were analyzed using the R2 platform. Cell viability, isobologram, and combination index analyses as a result of SSZ treatment with our without DFMO were carried out in NB cell cultures. Molecular protein-ligand docking was achieved using the GRAMM algorithm. Statistical analyses were performed with the Kruskal-Wallis test, 2log Pearson test, and Student’s t test. In this study, we show the clinical relevance of SPR in human NB tumors. We found that high SPR expression is significantly correlated to unfavorable NB characteristics like high age at diagnosis, MYCN amplification, and high INSS stage. SSZ inhibits the growth of NB cells in vitro, presumably due to the inhibition of SPR as predicted by computational docking of SSZ into SPR. Importantly, the combination of SSZ with DFMO produces synergistic antiproliferative effects in vitro. The results suggest the use of SSZ in combination with DFMO for further experiments, and possible prioritization as a novel therapy for the treatment of NB patients.
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novel interaction of ornithine decarboxylase with Sepiapterin Reductase regulates neuroblastoma cell proliferation
Journal of Molecular Biology, 2014Co-Authors: Ingo Lange, Dirk Geerts, David J Feith, Gabor Mocz, Jan Koster, Andre S BachmannAbstract:Ornithine decarboxylase (ODC) is the sentinel enzyme in polyamine biosynthesis. Both ODC and polyamines regulate cell division, proliferation, and apoptosis. Sepiapterin Reductase (SPR) catalyzes the last step in the biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase, and has been implicated in neurological diseases but not yet in cancer. In this study, we present compelling evidence that native ODC and SPR physically interact, and we defined the individual amino acid residues involved in both enzymes using in silico protein-protein docking simulations. The resulting heterocomplex is a surprisingly compact structure, featuring two energetically and structurally equivalent binding modes both in monomer and in dimer conformations. The novel interaction between ODC and SPR proteins was confirmed under physiological conditions by co-immunoprecipitation and co-localization in neuroblastoma (NB) cells. Importantly, we showed that siRNA (small interfering RNA)-mediated knockdown of SPR expression significantly reduced endogenous ODC enzyme activity in NB cells, thus demonstrating the biological relevance of the ODC-SPR interaction. Finally, in a cohort of 88 human NB tumors, we found that high SPR mRNA expression correlated significantly with poor survival prognosis using a Kaplan-Meier analysis (log-rank test, P=5 × 10(-4)), suggesting an oncogenic role for SPR in NB tumorigenesis. In conclusion, we showed that ODC binds SPR and thus propose a new concept in which two well-characterized biochemical pathways converge via the interaction of two enzymes. We identified SPR as a novel regulator of ODC enzyme activity and, based on clinical evidence, present a model in which SPR drives ODC-mediated malignant progression in NB.
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abstract 2495 Sepiapterin Reductase interacts with ornithine decarboxylase and regulates neuroblastoma proliferation
Cancer Research, 2012Co-Authors: Ingo Lange, Danalynn T Koomoa, Andre S BachmannAbstract:Ornithine Decarboxylase (ODC) is a key, rate-limiting enzyme in mammalian polyamine biosynthesis that is upregulated in various types of cancer including neuroblastoma (NB). MYCN is a transcription factor and proto-oncogene that has been shown to be a key prognostic factor associated with advanced stage NB. ODC is a transcriptional target of MYCN, and has been found to play a critical role in NB progression. Previous studies have shown that inhibition of ODC through drugs such as alpha-difluoromethylornithine (DFMO) depletes intracellular polyamine pools and induces G1 cell cycle arrest. Our previous studies have shown that the anti-proliferative effect of DFMO in NB involves upregulation of the cyclin dependent kinase inhibitor p27 and downregulation of MYCN. In a search for novel regulators of ODC, we recently discovered that Sepiapterin Reductase (SPR), a key enzyme in the biosynthesis of tetrahydrobiopterin, binds to ODC and may regulate ODC activity through a novel mechanism. Co-immunoprecipitation experiments using NB cell lysates show that ODC interacts with SPR. In addition, immunofluorescence staining and laser-scanning confocal microscopy confirm the co-localization of ODC and SPR. Furthermore, downregulation of SPR expression using siRNA targeting SPR results in significant inhibition of NB proliferation, without affecting ODC protein levels. These results suggest that the interaction between SPR and ODC may be critically important to ODC activity and function and may constitute a novel mechanism for the regulation of NB proliferation. This interaction may play a critical role in fundamental physiological and pathophysiological processes including the development and progression of NB. Understanding the novel interaction between ODC and SPR might play a crucial role for the development of new drugs targeting SPR for the treatment of NB and other MYC/ODC-driven diseases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2495. doi:1538-7445.AM2012-2495
Setsuko Katoh - One of the best experts on this subject based on the ideXlab platform.
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Sepiapterin Reductase gene disrupted mice suffer from hypertension with fluctuation and bradycardia
Physiological Reports, 2017Co-Authors: Chiho Sumiichinose, Hiroshi Ichinose, Setsuko Katoh, Yui Suganuma, Taiki Kano, Noriko Ihira, Hiroko Nomura, Kazuhisa Ikemoto, Tadayoshi Hata, Kazunao KondoAbstract:Abstract (6 R )‐l‐ erythro ‐5,6,7,8‐Tetrahydrobiopterin (BH4) is an essential cofactor for monoamine and nitric oxide (NO) production. Sepiapterin Reductase (SPR) catalyzes the final step in BH4 biosynthesis. We analyzed the cardiovascular function of adult Spr gene‐disrupted ( Spr −/− ) mice for the first time. After weaning, Spr −/− mice suffered from hypertension with fluctuation and bradycardia, while the monoamine contents in these mice were less than 10% of those in the wild‐type mice as a result of BH4 depletion. Heart rate variability analysis indicated the sympathetic dominant state in Spr −/− mice. The endothelium‐dependent vascular relaxation in response to acetylcholine was significantly impaired in Spr −/− mice after sexual maturation (above 4 months old). Protein amounts of α 1 adrenergic receptor and eNOS in the aorta were not altered. Spr −/− mice exhibited hypoglycemia and elevation of plasma renin activity. Our results suggest that the hypertension with fluctuation and bradycardia of Spr −/− mice would be caused by an imbalance of sympathetic and parasympathetic input and impaired nitric oxide production in endothelial cells. We suggest an important role of BH4 and SPR in age‐related hypertension and a possible relationship with the cardiovascular instabilities in autonomic diseases, including Parkinson9s disease and spinal cord injury.
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A brain-specific decrease of the tyrosine hydroxylase protein in Sepiapterin Reductase-null mice--as a mouse model for Parkinson's disease.
Biochemical and Biophysical Research Communications, 2008Co-Authors: Chisato Takazawa, Hiroshi Ichinose, Kengo Fujimoto, Daigo Homma, Chiho Sumi-ichinose, Takahide Nomura, Setsuko KatohAbstract:Abstract Sepiapterin Reductase (SPR) is an enzyme that acts in the third and final step of tetrahydrobiopterin (BH4) biosynthesis. The human Spr gene locates within the region of 2.5 MB mapped to PARK3, an autosomal dominant form of familial Parkinson’s diseases. In order to explore the role of SPR in the metabolism of BH4, we produced and analyzed Spr-deficient mice. Most of Spr-null mice survived beyond two weeks. Whereas the BH4 contents in the homozygous mutant mice were greatly decreased than those in wild-type and heterozygous mice, the substantial amounts of BH4 were remained even 17 days after delivery. Spr-null mice exhibited severe monoamine deficiencies and a tremor-like phenotype after weaning. The amount of TH protein in the brain of Spr-null mice was less than 10% of wild-type, while TH protein in the adrenal, phenylalanine hydroxylase protein in the liver, and nNOS in the brain were not altered. These data suggest an essential role of SPR in the biosynthesis of BH4, and that the SPR gene could be a candidate gene for PARK3.
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mutational analysis of sites in Sepiapterin Reductase phosphorylated by ca2 calmodulin dependent protein kinase ii
Biochimica et Biophysica Acta, 2002Co-Authors: Kengo Fujimoto, Susumu Y Takahashi, Setsuko KatohAbstract:Sepiapterin Reductase (SPR) catalyzes the last step in the pathway of tetrahydrobiopterin biosynthesis in tissues. SPR is phosphorylated by Ca2+-dependent protein kinases, which indicates that Ca2+-activated protein kinases may play a role in the regulation of SPR in vivo. Phosphorylation sites of rat Sepiapterin Reductase (rSPR) by Ca2+/calmodulin-dependent protein kinase II were determined in the present study. Using specific monoclonal anti-phospho-Ser and -Thr antibodies, we found that only Ser residues of rSPR were phosphorylated. We constructed several point mutants of SPR by systematically replacing the three Ser residues by Ala ones. These mutants showed that all three Ser residues, i.e. S46, S196, and S214, of rSPR were phosphorylated. We also recognized that only Ser-213 of human SPR was phosphorylated. Each of these serine residues in SPR was found in the consensus sequence (Arg-X-X-Ser/Thr) of the phosphorylation site.
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genomic organization and chromosomal localization of the human Sepiapterin Reductase gene
Biochemical and Biophysical Research Communications, 1998Co-Authors: Tamae Ohye, Setsuko Katoh, Toshiharu Nagatsu, Tadaaki Hori, Hiroshi IchinoseAbstract:Abstract Sepiapterin Reductase (SPR) catalyzes the final step of the biosynthetic pathway of tetrahydrobiopterin, which is an essential cofactor for aromatic amino acid hydroxylases and nitric oxide synthases. To aid the analysis of any possible human diseases caused by mutations in SPR, we have cloned and characterized the human SPR gene. The gene is composed of three exons spanning approximately 4 kilobases. The transcriptional starting point was determined around the cytosine nucleotide at position −81 by primer extension and RT-PCR analyses. There was no typical TATA-box within 300 bp from the transcriptional starting point. We found the Sp1-binding consensus sequence in the 5′-flanking region. The human SPR gene was mapped to chromosome band 2p13 by fluorescence in situ hybridization.
Beat Thöny - One of the best experts on this subject based on the ideXlab platform.
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Clinical Chemistry 47:3 477–485 (2001) Molecular Diagnostics and Genetics Diagnosis of Dopa-responsive Dystonia and Other Tetrahydrobiopterin Disorders by the Study of Biopterin Metabolism in Fibroblasts
2013Co-Authors: Luisa Bonafé, Beat Thöny, Walter Leimbacher, Lucja Kierat, Nenad BlauAbstract:(BH 4) defects are inherited disorders characterized by monoamine neurotransmitter deficiency with decreased activity of one of the BH 4-metabolizing enzymes. The aim of the study was to determine the utility of cultured skin fibroblasts for the diagnosis of these diseases. Methods: Neopterin and biopterin production and GTP cyclohydrolase I (GTPCH) activity were measured in cytokine-stimulated fibroblasts; 6-pyruvoyltetrahydropterin synthase (PTPS), Sepiapterin Reductase (SR), and dihydropteridine Reductase (DHPR) activities were measured in unstimulated fibroblasts. 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 amniocyt
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child neurology paroxysmal stiffening upward gaze and hypotonia hallmarks of Sepiapterin Reductase deficiency
Neurology, 2012Co-Authors: Patricia Dill, Beat Thöny, Nenad Blau, Michael Wagner, A Somerville, Peter WeberAbstract:Sepiapterin Reductase deficiency (SRD) is a dopa-sensitive neurotransmitter disorder, caused by mutation of the SPR gene located on chromosome 2p14-p12.1 To date, 31 patients with 14 mutations have been diagnosed (BIODEF database, update November 2010, www.biopku.org). While classic tetrahydrobiopterin deficiencies present with hyperphenylalaninemia and deficiency of monoamine neurotransmitters, SRD is typically associated with normal phenylalanine levels in blood and pterins in urine2 and not detectable by neonatal screening for phenylketonuria. This implies how important it is to diagnose this condition clinically, in order to provide timely and proper treatment. A summary of the pathophysiology and biochemical pathway is provided by Bonafe et al.2 With the following case report and review of 21 published cases,2,–,10 we elucidate the clinical features of SRD as well as the diagnostic strategy and therapeutic approach. We present a 5-month-old girl, the first and only child born to consanguineous Turkish parents. The parents described the girl's abnormal movements at 3 months of age as sudden stiffening of the whole body, extension of the extremities, upward gaze, and chewing movements lasting for several minutes often after meals, which we also could observe during her hospital stay. Pregnancy and delivery were uneventful. Birthweight, length, and head circumference were within normal ranges. During EEG, a few episodes with chewing movements could be recorded, but no epileptic discharges were evident. The brain MRI was unremarkable. We suspected gastroesophageal reflux and started therapy with omeprazole. The parents reported that the episodes diminished. At 8 months of age, the patient was readmitted because the crises recurred with an increased frequency and duration of up to 25 minutes. During the episodes, the patient revealed circling movements of the hands and rhythmic tremor of the tongue in addition to the previously mentioned symptoms. Remarkably, the …
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Two Greek siblings with Sepiapterin Reductase deficiency
Molecular genetics and metabolism, 2008Co-Authors: Marcel M. Verbeek, Nico G Abeling, Beat Thöny, Nenad Blau, Michèl A.a.p. Willemsen, Ron A. Wevers, Aart J. Lagerwerf, Euthymia Vargiami, Dimitrios I. ZafeiriouAbstract:BACKGROUND: Sepiapterin Reductase (SR) deficiency is a rare inherited disorder of neurotransmitter metabolism; less than 25 cases have been described in the literature so far. METHODS: We describe the clinical history and extensive cerebrospinal fluid (CSF) and urine examination of two Greek siblings with the diagnosis of SR deficiency. The diagnosis was confirmed by enzyme activity measurement in cultured fibroblasts and by mutation analysis. RESULTS: Both patients suffered from a progressive and complex L-dopa responsive movement disorder. Very low concentrations of the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) were observed in CSF. CSF neopterin and biopterin concentrations were abnormal in one case only, whereas in both cases Sepiapterin concentrations were abnormally high and 5-hydroxytryptophan was undetectable. Urine concentrations of HVA, 5-HIAA and vanillyl mandelic acid (VMA) were decreased in both cases. Both patients had no detectable SR enzyme activity in primary dermal fibroblasts, and upon analysis of genomic DNA revealed the same homozygous point mutation introducing a premature stop codon into the reading frame of the SPR gene (mutant allele K251X). CONCLUSIONS: Our cases illustrate that, apart from HVA and 5-HIAA analysis, the specific quantification of Sepiapterin in CSF, rather than neopterin and biopterin alone, is crucial to the final diagnosis of SR deficiency. In addition, urinary concentrations of neurotransmitter metabolites may be abnormal in SR deficiency and may provide an initial indication of SR deficiency before CSF analysis is performed. The known, impressive beneficial response of SR deficient patients to treatment with L-dopa, is illustrated again in our cases.
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mutations in the bh4 metabolizing genes gtp cyclohydrolase i 6 pyruvoyl tetrahydropterin synthase Sepiapterin Reductase carbinolamine 4a dehydratase and dihydropteridine Reductase
Human Mutation, 2006Co-Authors: Beat Thöny, Nenad BlauAbstract:Tetrahydrobiopterin (BH(4)) deficiencies are a highly heterogeneous group of disorders with several hundred patients, and so far a total of 193 different mutant alleles or molecular lesions identified in the GTP cyclohydrolase I (GTPCH), 6-pyruvoyl-tetrahydropterin synthase (PTPS), Sepiapterin Reductase (SR), carbinolamine-4a-dehydratase (PCD), or dihydropteridine Reductase (DHPR) genes. The spectrum of mutations causing a reduction in one of the three biosynthetic (GTPCH, PTPS, and SR) or the two regenerating enzymes (PCD and DHPR) is tabulated and reviewed. Furthermore, current genomic variations or SNPs are also compiled. Mutations in GCH1 are scattered over the entire gene, and only 5 out of 104 mutant alleles, present in a homozygous state, are reported to cause the autosomal recessive form of inheritable hyperphenylalaninemia (HPA) associated with monoamine neurotransmitter deficiency. Almost all other 99 different mutant alleles in GCH1 are observed together with a wild-type allele and cause Dopa-responsive dystonia (DRD, Segawa disease) in a dominant fashion with reduced penetrance. Compound heterozygous or homozygous mutations are spread over the entire genes for PTS with 44 mutant alleles, for PCBD with nine mutant alleles, and for QDPR with 29 mutant alleles. These mutations cause an autosomal recessive inherited form of HPA, mostly accompanied by a deficiency of the neurotransmitters dopamine and serotonin. Lack of Sepiapterin Reductase activity, an autosomal recessive variant of BH(4) deficiency presenting without HPA, was diagnosed in patients with seven different mutant alleles in the SPR gene in exons 2 or 3 or in intron 2. Details on all mutations presented here are constantly updated in the BIOMDB database (www.bh4.org).
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Sepiapterin Reductase deficiency an autosomal recessive DOPA-responsive dystonia.
Molecular genetics and metabolism, 2006Co-Authors: Nico G Abeling, Marinus Duran, Henk D Bakker, Lida Stroomer, Beat Thöny, Nenad Blau, Jan Booij, Bwee Tien Poll-theAbstract:The diagnosis of a 14-year-old girl with a new homoallelic mutation in the Sepiapterin Reductase (SR) gene is reported. Initially she presented at the age of 2 with hypotonia and mild cognitive developmental delay, and was diagnosed as having mild methylmalonic aciduria, which was recently identified as methylmalonylCoA racemase deficiency, a new defect in valine-isoleucine metabolism. After a 12-year progression of her neurologic condition, which had made her wheelchair-bound at the age of 6, dystonia with diurnal variation had become apparent. At the age of 14 this finding led to rapid diagnosis of SR deficiency. The diagnostic approach with CSF neurotransmitter and pterins analysis and combined phenylalanine/BH(4) loading test, and finally measurement of Sepiapterin in CSF is illustrative for the diagnosis of SR deficiency. As in all other patients with this new defect, very low levels of homovanillic acid and 5-hydroxyindoleacetic acid and high levels of biopterin and Sepiapterin in the CSF are the diagnostic hallmark. The girl improved dramatically on treatment with L-DOPA and 5-hydroxytryptophan. The initial diagnosis of methylmalonic aciduria may afterwards be considered to have not significantly contributed to her clinical condition and only has led to a long delay of the clinically relevant diagnosis of SR deficiency. Although the clinical condition of this recently recognized autosomal recessive defect in pterin metabolism is complex and many symptoms can occur in variable severity and time of onset, dystonia with diurnal variation is a characteristic finding, as shown in nearly all patients described so far. The rapid and favourable response on treatment with L-DOPA warrants the classification of SR deficiency as another autosomal recessive type of DOPA-responsive dystonia (DRD). This classification is important to improve the awareness of clinicians that more than one metabolic defect can underlie the phenotype of a DOPA-responsive dystonic disorder and that dystonia should always trigger a rapid diagnosis of the underlying neurotransmitter synthesis defect, in view of the excellent treatability of a DRD.
