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Pesquisa : D03.633.100.733.631.202 [Categoria DeCS]
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[PMID]:28915855
[Au] Autor:Chaiyasap P; Ittiwut C; Srichomthong C; Sangsin A; Suphapeetiporn K; Shotelersuk V
[Ad] Endereço:Center of Excellence for Medical Genetics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.
[Ti] Título:Massive parallel sequencing as a new diagnostic approach for phenylketonuria and tetrahydrobiopterin-deficiency in Thailand.
[So] Source:BMC Med Genet;18(1):102, 2017 Sep 16.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Hyperphenylalaninemia (HPA) can be classified into phenylketonuria (PKU) which is caused by mutations in the phenylalanine hydroxylase (PAH) gene, and BH4 deficiency caused by alterations in genes involved in tetrahydrobiopterin (BH4) biosynthesis pathway. Dietary restriction of phenylalanine is considered to be the main treatment of PKU to prevent irreversible intellectual disability. However, the same dietary intervention in BH4 deficiency patients is not as effective, as BH4 is also a cofactor in many neurotransmitter syntheses. METHOD: We utilized next generation sequencing (NGS) technique to investigate four unrelated Thai patients with hyperphenylalaninemia. RESULT: We successfully identified all eight mutant alleles in PKU or BH4-deficiency associated genes including three novel mutations, one in PAH and two in PTS, thus giving a definite diagnosis to these patients. Appropriate management can then be provided. CONCLUSION: This study identified three novel mutations in either the PAH or PTS gene and supported the use of NGS as an alternative molecular genetic approach for definite diagnosis of hyperphenylalaninemia, thus leading to proper management of these patients in Thailand.
[Mh] Termos MeSH primário: Grupo com Ancestrais do Continente Asiático/genética
Sequenciamento de Nucleotídeos em Larga Escala
Fenilalanina Hidroxilase/genética
Fenilcetonúrias/diagnóstico
Fósforo-Oxigênio Liases/genética
[Mh] Termos MeSH secundário: Alelos
Sequência de Aminoácidos
Biopterina/análogos & derivados
Biopterina/biossíntese
Exoma
Feminino
Genótipo
Seres Humanos
Lactente
Masculino
Fenilcetonúrias/genética
Análise de Sequência de DNA
Tailândia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
22150-76-1 (Biopterin); EC 1.14.16.1 (Phenylalanine Hydroxylase); EC 4.6.- (Phosphorus-Oxygen Lyases); EC 4.6.10 (6-pyruvoyltetrahydropterin synthase); EGX657432I (sapropterin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170917
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-017-0464-x


  2 / 3645 MEDLINE  
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[PMID]:28679641
[Au] Autor:Porta F; Spada M; Ponzone A
[Ad] Endereço:Department of Pediatrics, University of Torino, Torino, Italy porta.franc@gmail.com.
[Ti] Título:Early Screening for Tetrahydrobiopterin Responsiveness in Phenylketonuria.
[So] Source:Pediatrics;140(2), 2017 Aug.
[Is] ISSN:1098-4275
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Since 2007, synthetic tetrahydrobiopterin (BH4) has been approved as a therapeutic option in BH4-responsive phenylketonuria (PKU) and since 2015 extended to infants younger than 4 years in Europe. The current definition of BH4 responsiveness relies on the observation of a 20% to 30% blood phenylalanine (Phe) decrease after BH4 administration, under nonstandardized conditions. By this definition, however, patients with the same genotype or even the same patients were alternatively reported as responsive or nonresponsive to the cofactor. These inconsistencies are troubling, as frustrating patient expectations and impairing cost-effectiveness of BH4-therapy. Here we tried a quantitative procedure through the comparison of the outcome of a simple Phe and a combined Phe plus BH4 loading in a series of infants with PKU, most of them harboring genotypes already reported as BH4 responsive. Under these ideal conditions, blood Phe clearance did not significantly differ after the 2 types of loading, and a 20% to 30% decrease of blood Phe occurred irrespective of BH4 administration in milder forms of PKU. Such early screening for BH4 responsiveness, based on a quantitative assay, is essential for warranting an evidence-based and cost-effective therapy in those patients with PKU eventually but definitely diagnosed as responsive to the cofactor.
[Mh] Termos MeSH primário: Biopterina/análogos & derivados
Diagnóstico Precoce
Programas de Rastreamento
Fenilalanina/sangue
Fenilcetonúrias/sangue
Fenilcetonúrias/tratamento farmacológico
[Mh] Termos MeSH secundário: Biopterina/sangue
Biopterina/uso terapêutico
Análise Mutacional de DNA
Seres Humanos
Lactente
Fenilalanina Hidroxilase/sangue
Fenilalanina Hidroxilase/genética
Fenilcetonúrias/diagnóstico
Fenilcetonúrias/genética
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
22150-76-1 (Biopterin); 47E5O17Y3R (Phenylalanine); EC 1.14.16.1 (Phenylalanine Hydroxylase); EGX657432I (sapropterin)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170828
[Lr] Data última revisão:
170828
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE


  3 / 3645 MEDLINE  
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[PMID]:28632534
[Au] Autor:Rahmania L; Orbegozo D; Su F; Taccone FS; Vincent JL; De Backer D
[Ad] Endereço:From the Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
[Ti] Título:Administration of Tetrahydrobiopterin (BH4) Protects the Renal Microcirculation From Ischemia and Reperfusion Injury.
[So] Source:Anesth Analg;125(4):1253-1260, 2017 Oct.
[Is] ISSN:1526-7598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Abdominal aortic aneurysm surgery with suprarenal cross-clamping is often associated with renal injury. Although the mechanism underlying such injury is unclear, tissue ischemia and reperfusion, which induces endothelial dysfunction and decreases the availability of tetrahydrobiopterin (BH4), may play a role. We evaluated whether BH4 administration prevents renal ischemia/reperfusion injury in an animal model of aortic cross-clamping. METHODS: Nineteen anesthetized, mechanically ventilated, and invasively monitored adult sheep were randomized into 3 groups: sham animals (n = 5) that underwent surgical preparation but no aortic clamping; an ischemia/reperfusion group (n = 7), where the aorta was clamped above the renal arteries for 1 hour, and a BH4 group (n = 7), in which animals received 20 mg/kg of BH4 followed by aortic cross-clamp for 1 hour. Animals were followed for a maximum of 6 hours after reperfusion. The renal microcirculation was evaluated at baseline (before clamping), and 1, 4, and 6 hours after reperfusion using side-stream dark field videomicroscopy. The renal lactate-to-pyruvate ratio was evaluated using microdialysis. The primary outcome was the change in proportion of small perfused vessels before and after injury. Secondary outcomes were renal tissue redox state and renal function. RESULTS: Ischemia/reperfusion injury was associated with increases in heart rate and mean arterial pressure, which were blunted by BH4 administration. From the first to the sixth hour after reperfusion, the small vessel density (estimated mean difference [EMD], 1.03; 95% confidence interval [CI], 0.41-1.64; P = .003), perfused small vessel density (EMD, 0.84; 95% CI, 0.29-1.39; P = .005), and proportion of perfused small vessels (EMD, 8.60; 95% CI, 0.85-16.30; P = .031) were altered less in the BH4 than in the ischemia/reperfusion group. The renal lactate-to-pyruvate ratios were lower in the cortex in the BH4 than in the ischemia/reperfusion group from the first to the sixth hour after reperfusion (EMD, -19.16; 95% CI, -11.06 to 33.16; P = .002) and in the medulla from the first to the fourth hour (EMD, -26.62; 95% CI, -18.32 to 38.30; P = .020; and EMD, -8.68; 95% CI, -5.96 to 12.65; P = .019). At the sixth hour, serum creatinine was lower in the BH4 than in the ischemia/reperfusion group (EMD, -3.36; 95% CI, -0.29 to 1.39; P = .026). CONCLUSIONS: In this sheep model of renal ischemia/reperfusion, BH4 pretreatment reduced renal microvascular injury and improved renal metabolism and function. Further work is needed to clarify the potential role of BH4 in ischemia/reperfusion injury.
[Mh] Termos MeSH primário: Biopterina/análogos & derivados
Isquemia/prevenção & controle
Rim/efeitos dos fármacos
Microcirculação/efeitos dos fármacos
Circulação Renal/efeitos dos fármacos
Traumatismo por Reperfusão/prevenção & controle
[Mh] Termos MeSH secundário: Animais
Biopterina/administração & dosagem
Feminino
Isquemia/fisiopatologia
Rim/irrigação sanguínea
Rim/fisiologia
Microcirculação/fisiologia
Substâncias Protetoras/administração & dosagem
Distribuição Aleatória
Circulação Renal/fisiologia
Traumatismo por Reperfusão/fisiopatologia
Ovinos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protective Agents); 22150-76-1 (Biopterin); EGX657432I (sapropterin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1213/ANE.0000000000002131


  4 / 3645 MEDLINE  
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[PMID]:28596000
[Au] Autor:Xue J; Yu C; Sheng W; Zhu W; Luo J; Zhang Q; Yang H; Cao H; Wang W; Zhou J; Wu J; Cao P; Chen M; Ding WQ; Cao J; Zhang S
[Ad] Endereço:School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, China; Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions and Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, Ch
[Ti] Título:The Nrf2/GCH1/BH4 Axis Ameliorates Radiation-Induced Skin Injury by Modulating the ROS Cascade.
[So] Source:J Invest Dermatol;137(10):2059-2068, 2017 Oct.
[Is] ISSN:1523-1747
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Radiation-induced skin injury is a common side effect of radiotherapy and can limit the duration and dose of radiotherapy. Most early work focused on elimination of reactive oxygen species (ROS) after radiation; however, less is known about the mechanisms underlying amplification of ROS and consequent skin injury by radiation. 5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for all nitric oxide synthases. Inadequate availability of BH4 leads to uncoupling of nitric oxide synthases and production of highly oxidative radicals. In this study, we demonstrated that radiation disrupted BH4, which resulted in nitric oxide synthases uncoupling and augmented radiation-induced ROS. Overexpression of GTP cyclohydrolase I (GCH1), the rate-limiting enzyme for BH4 synthesis, restored cellular BH4 levels and nitric oxide production and decreased radiation-induced ROS. GCH1 also protected skin cells and rat skins against radiation-induced damage. We found that GCH1 was regulated by NF-E2-related factor 2, a key mediator of the cellular antioxidant response. Importantly, we identified GCH1 as a key effector for NF-E2-related factor 2-mediated protection against radiation-induced skin injury by inhibiting ROS production. Taken together, the findings of this study illustrate the key role of the NF-E2-related factor 2/GCH1/BH4 axis during radiation-induced skin damage.
[Mh] Termos MeSH primário: Biopterina/análogos & derivados
GTP Cicloidrolase/biossíntese
Fator 2 Relacionado a NF-E2/biossíntese
Lesões Experimentais por Radiação/metabolismo
Espécies Reativas de Oxigênio/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose
Biopterina/biossíntese
Células Cultivadas
Seres Humanos
Camundongos
Camundongos Knockout
Oxirredução
Lesões Experimentais por Radiação/patologia
Pele/metabolismo
Pele/patologia
Pele/efeitos da radiação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NF-E2-Related Factor 2); 0 (Reactive Oxygen Species); 22150-76-1 (Biopterin); EC 3.5.4.16 (GTP Cyclohydrolase); EGX657432I (sapropterin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170610
[St] Status:MEDLINE


  5 / 3645 MEDLINE  
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[PMID]:28350856
[Au] Autor:Kim DH; Shin M; Jung SH; Kim YJ; Jones WD
[Ad] Endereço:Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea.
[Ti] Título:A fat-derived metabolite regulates a peptidergic feeding circuit in Drosophila.
[So] Source:PLoS Biol;15(3):e2000532, 2017 Mar.
[Is] ISSN:1545-7885
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Here, we show that the enzymatic cofactor tetrahydrobiopterin (BH4) inhibits feeding in Drosophila. BH4 biosynthesis requires the sequential action of the conserved enzymes Punch, Purple, and Sepiapterin Reductase (Sptr). Although we observe increased feeding upon loss of Punch and Purple in the adult fat body, loss of Sptr must occur in the brain. We found Sptr expression is required in four adult neurons that express neuropeptide F (NPF), the fly homologue of the vertebrate appetite regulator neuropeptide Y (NPY). As expected, feeding flies BH4 rescues the loss of Punch and Purple in the fat body and the loss of Sptr in NPF neurons. Mechanistically, we found BH4 deficiency reduces NPF staining, likely by promoting its release, while excess BH4 increases NPF accumulation without altering its expression. We thus show that, because of its physically distributed biosynthesis, BH4 acts as a fat-derived signal that induces satiety by inhibiting the activity of the NPF neurons.
[Mh] Termos MeSH primário: Biopterina/análogos & derivados
Proteínas de Drosophila/fisiologia
Drosophila melanogaster/metabolismo
[Mh] Termos MeSH secundário: Oxirredutases do Álcool/genética
Oxirredutases do Álcool/fisiologia
Animais
Biopterina/genética
Biopterina/metabolismo
Biopterina/fisiologia
Tamanho Corporal
Proteínas de Drosophila/genética
Proteínas de Drosophila/metabolismo
Drosophila melanogaster/genética
Drosophila melanogaster/fisiologia
Corpo Adiposo/metabolismo
Comportamento Alimentar
Técnicas de Silenciamento de Genes
Testes Genéticos
MicroRNAs/fisiologia
Modelos Biológicos
Neuropeptídeos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drosophila Proteins); 0 (MicroRNAs); 0 (Neuropeptides); 0 (iab-4 microRNA, Drosophila); 0 (neuropeptide F, Drosophila); 22150-76-1 (Biopterin); EC 1.1.- (Alcohol Oxidoreductases); EC 1.1.1.153 (sepiapterin reductase); EGX657432I (sapropterin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170629
[Lr] Data última revisão:
170629
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170329
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pbio.2000532


  6 / 3645 MEDLINE  
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[PMID]:28235150
[Au] Autor:Feldmann R; Wolfgart E; Weglage J; Rutsch F
[Ad] Endereço:Department of General Pediatrics, Münster University Children's Hospital, Münster, Germany.
[Ti] Título:Sapropterin treatment does not enhance the health-related quality of life of patients with phenylketonuria and their parents.
[So] Source:Acta Paediatr;106(6):953-959, 2017 Jun.
[Is] ISSN:1651-2227
[Cp] País de publicação:Norway
[La] Idioma:eng
[Ab] Resumo:AIM: Sapropterin causes reductions in blood phenylalanine concentrations in sensitive patients with phenylketonuria (PKU). We examined whether the subsequent relaxation of dietary restrictions influenced the quality of life (QoL) of patients and parents. METHODS: The study cohort comprised 112 patients with PKU followed at the metabolic centre at Münster University Children's Hospital, Germany, from 2012 to 2015. A sapropterin response was defined as a ≥30% reduction in blood phenylalanine levels. The QoL of 38 children and adolescents from the study cohort, with a mean age of 12.4 (range 6.6-18.7) years, was assessed in an outpatient setting and 49 parents of children with PKU also commented on their child's QoL and their own. The participants' QoL was assessed before the start of therapy, and again after six months, using self-report questionnaires. RESULTS: After six months of continuous therapy or diet, QoL was largely unchanged in the patients, according to their self-reports and the parental reports. QoL also remained unchanged in the parents. CONCLUSION: Sapropterin did not seem to improve QoL in PKU patients and their parents. Patients with PKU had already reached high levels of QoL following classic diets, and these levels were not easily improved by sapropterin.
[Mh] Termos MeSH primário: Biopterina/análogos & derivados
Fenilcetonúrias/tratamento farmacológico
[Mh] Termos MeSH secundário: Adolescente
Adulto
Biopterina/uso terapêutico
Criança
Pré-Escolar
Estudos de Coortes
Feminino
Seres Humanos
Masculino
Meia-Idade
Pais/psicologia
Fenilcetonúrias/dietoterapia
Fenilcetonúrias/psicologia
Qualidade de Vida
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
22150-76-1 (Biopterin); EGX657432I (sapropterin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170630
[Lr] Data última revisão:
170630
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170225
[St] Status:MEDLINE
[do] DOI:10.1111/apa.13799


  7 / 3645 MEDLINE  
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[PMID]:28158561
[Au] Autor:Shen JS; Arning E; West ML; Day TS; Chen S; Meng XL; Forni S; McNeill N; Goker-Alpan O; Wang X; Ashcraft P; Moore DF; Cheng SH; Schiffmann R; Bottiglieri T
[Ad] Endereço:Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX 75226, USA.
[Ti] Título:Tetrahydrobiopterin deficiency in the pathogenesis of Fabry disease.
[So] Source:Hum Mol Genet;26(6):1182-1192, 2017 Mar 15.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Fabry disease is caused by deficient activity of α-galactosidase A and subsequent accumulation of glycosphingolipids (mainly globotriaosylceramide, Gb3), leading to multisystem organ dysfunction. Oxidative stress and nitric oxide synthase (NOS) uncoupling are thought to contribute to Fabry cardiovascular diseases. We hypothesized that decreased tetrahydrobiopterin (BH4) plays a role in the pathogenesis of Fabry disease. We found that BH4 was decreased in the heart and kidney but not in the liver and aorta of Fabry mice. BH4 was also decreased in the plasma of female Fabry patients, which was not corrected by enzyme replacement therapy (ERT). Gb3 levels were inversely correlated with BH4 levels in animal tissues and cultured patient cells. To investigate the role of BH4 deficiency in disease phenotypes, 12-month-old Fabry mice were treated with gene transfer-mediated ERT or substrate reduction therapy (SRT) for 6 months. In the Fabry mice receiving SRT but not ERT, BH4 deficiency was restored, concomitant with ameliorated cardiac and renal hypertrophy. Additionally, glutathione levels were decreased in Fabry mouse tissues in a sex-dependent manner. Renal BH4 levels were closely correlated with glutathione levels and inversely correlated with cardiac and kidney weight. In conclusion, this study showed that BH4 deficiency occurs in Fabry disease and may contribute to the pathogenesis of the disease through oxidative stress associated with a reduced antioxidant capacity of cells and NOS uncoupling. This study also suggested dissimilar efficacy of ERT and SRT in correcting pre-existing pathologies in Fabry disease.
[Mh] Termos MeSH primário: Biopterina/análogos & derivados
Terapia de Reposição de Enzimas
Doença de Fabry/genética
alfa-Galactosidase/genética
[Mh] Termos MeSH secundário: Animais
Biopterina/deficiência
Biopterina/genética
Biopterina/metabolismo
Modelos Animais de Doenças
Doença de Fabry/mortalidade
Doença de Fabry/fisiopatologia
Feminino
Glutationa/metabolismo
Glicoesfingolipídeos/metabolismo
Seres Humanos
Rim/metabolismo
Rim/patologia
Camundongos
Miocárdio/metabolismo
Miocárdio/patologia
Óxido Nítrico Sintase/genética
Óxido Nítrico Sintase/metabolismo
Estresse Oxidativo/genética
alfa-Galactosidase/biossíntese
alfa-Galactosidase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glycosphingolipids); 22150-76-1 (Biopterin); EC 1.14.13.39 (Nitric Oxide Synthase); EC 3.2.1.22 (alpha-Galactosidase); EGX657432I (sapropterin); GAN16C9B8O (Glutathione)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170515
[Lr] Data última revisão:
170515
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170204
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx032


  8 / 3645 MEDLINE  
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[PMID]:28132689
[Au] Autor:Anikster Y; Haack TB; Vilboux T; Pode-Shakked B; Thöny B; Shen N; Guarani V; Meissner T; Mayatepek E; Trefz FK; Marek-Yagel D; Martinez A; Huttlin EL; Paulo JA; Berutti R; Benoist JF; Imbard A; Dorboz I; Heimer G; Landau Y; Ziv-Strasser L; Malicdan MCV; Gemperle-Britschgi C; Cremer K; Engels H; Meili D; Keller I; Bruggmann R; Strom TM; Meitinger T; Mullikin JC; Schwartz G; Ben-Zeev B; Gahl WA; Harper JW; Blau N; Hoffmann GF; Prokisch H; Opladen T; Schiff M
[Ad] Endereço:Metabolic Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel; The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel Hashomer 52621, Israel. Electronic
[Ti] Título:Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability.
[So] Source:Am J Hum Genet;100(2):257-266, 2017 Feb 02.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Phenylketonuria (PKU, phenylalanine hydroxylase deficiency), an inborn error of metabolism, can be detected through newborn screening for hyperphenylalaninemia (HPA). Most individuals with HPA harbor mutations in the gene encoding phenylalanine hydroxylase (PAH), and a small proportion (2%) exhibit tetrahydrobiopterin (BH ) deficiency with additional neurotransmitter (dopamine and serotonin) deficiency. Here we report six individuals from four unrelated families with HPA who exhibited progressive neurodevelopmental delay, dystonia, and a unique profile of neurotransmitter deficiencies without mutations in PAH or BH metabolism disorder-related genes. In these six affected individuals, whole-exome sequencing (WES) identified biallelic mutations in DNAJC12, which encodes a heat shock co-chaperone family member that interacts with phenylalanine, tyrosine, and tryptophan hydroxylases catalyzing the BH -activated conversion of phenylalanine into tyrosine, tyrosine into L-dopa (the precursor of dopamine), and tryptophan into 5-hydroxytryptophan (the precursor of serotonin), respectively. DNAJC12 was undetectable in fibroblasts from the individuals with null mutations. PAH enzyme activity was reduced in the presence of DNAJC12 mutations. Early treatment with BH and/or neurotransmitter precursors had dramatic beneficial effects and resulted in the prevention of neurodevelopmental delay in the one individual treated before symptom onset. Thus, DNAJC12 deficiency is a preventable and treatable cause of intellectual disability that should be considered in the early differential diagnosis when screening results are positive for HPA. Sequencing of DNAJC12 may resolve any uncertainty and should be considered in all children with unresolved HPA.
[Mh] Termos MeSH primário: Distonia/genética
Deficiência Intelectual/genética
Fenilcetonúrias/genética
Proteínas Repressoras/genética
[Mh] Termos MeSH secundário: Alelos
Sequência de Aminoácidos
Biopterina/análogos & derivados
Biopterina/metabolismo
Estudos de Casos e Controles
Dopamina/deficiência
Dopamina/metabolismo
Éxons
Feminino
Fibroblastos/metabolismo
Deleção de Genes
Estudo de Associação Genômica Ampla
Proteínas de Choque Térmico HSP70/genética
Seres Humanos
Masculino
Linhagem
Fenilalanina/metabolismo
Fenilalanina Hidroxilase/genética
Serotonina/deficiência
Serotonina/metabolismo
Triptofano/metabolismo
Triptofano Hidroxilase/genética
Triptofano Hidroxilase/metabolismo
Tirosina/metabolismo
Tirosina 3-Mono-Oxigenase/genética
Tirosina 3-Mono-Oxigenase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HSP70 Heat-Shock Proteins); 0 (JDP1 protein, human); 0 (Repressor Proteins); 22150-76-1 (Biopterin); 333DO1RDJY (Serotonin); 42HK56048U (Tyrosine); 47E5O17Y3R (Phenylalanine); 8DUH1N11BX (Tryptophan); EC 1.14.16.1 (Phenylalanine Hydroxylase); EC 1.14.16.2 (Tyrosine 3-Monooxygenase); EC 1.14.16.4 (Tryptophan Hydroxylase); EGX657432I (sapropterin); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170802
[Lr] Data última revisão:
170802
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170131
[St] Status:MEDLINE


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[PMID]:28128438
[Au] Autor:Chuaiphichai S; Crabtree MJ; Mcneill E; Hale AB; Trelfa L; Channon KM; Douglas G
[Ad] Endereço:British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, Oxford, UK.
[Ti] Título:A key role for tetrahydrobiopterin-dependent endothelial NOS regulation in resistance arteries: studies in endothelial cell tetrahydrobiopterin-deficient mice.
[So] Source:Br J Pharmacol;174(8):657-671, 2017 Apr.
[Is] ISSN:1476-5381
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND PURPOSE: The cofactor tetrahydrobiopterin (BH4) is a critical regulator of endothelial NOS (eNOS) function, eNOS-derived NO and ROS signalling in vascular physiology. To determine the physiological requirement for de novo endothelial cell BH4 synthesis for the vasomotor function of resistance arteries, we have generated a mouse model with endothelial cell-specific deletion of Gch1, encoding GTP cyclohydrolase 1 (GTPCH), an essential enzyme for BH4 biosynthesis, and evaluated BH4-dependent eNOS regulation, eNOS-derived NO and ROS generation. EXPERIMENTAL APPROACH: The reactivity of mouse second-order mesenteric arteries was assessed by wire myography. High performance liquid chromatography was used to determine BH4, BH2 and biopterin. Western blotting was used for expression analysis. KEY RESULTS: Gch1 Tie2cre mice demonstrated reduced GTPCH protein and BH4 levels in mesenteric arteries. Deficiency in endothelial cell BH4 leads to eNOS uncoupling, increased ROS production and loss of NO generation in mesenteric arteries of Gch1 Tie2cre mice. Gch1 Tie2cre mesenteric arteries had enhanced vasoconstriction to U46619 and phenylephrine, which was abolished by L-NAME. Endothelium-dependent vasodilatations to ACh and SLIGRL were impaired in mesenteric arteries from Gch1 Tie2cre mice, compared with those from wild-type littermates. Loss of eNOS-derived NO-mediated vasodilatation was associated with increased eNOS-derived H O and cyclooxygenase-derived vasodilator in Gch1 Tie2cre mesenteric arteries. CONCLUSIONS AND IMPLICATIONS: Endothelial cell Gch1 and BH4-dependent eNOS regulation play pivotal roles in maintaining vascular homeostasis in resistance arteries. Therefore, targeting vascular Gch1 and BH4 biosynthesis may provide a novel therapeutic target for the prevention and treatment of microvascular dysfunction in patients with cardiovascular disease.
[Mh] Termos MeSH primário: Biopterina/análogos & derivados
Células Endoteliais/metabolismo
Artérias Mesentéricas/citologia
Artérias Mesentéricas/metabolismo
Óxido Nítrico Sintase Tipo III/metabolismo
[Mh] Termos MeSH secundário: Animais
Biopterina/deficiência
Biopterina/metabolismo
Células Cultivadas
GTP Cicloidrolase/deficiência
GTP Cicloidrolase/genética
GTP Cicloidrolase/metabolismo
Masculino
Camundongos
Camundongos Knockout
Óxido Nítrico/biossíntese
Óxido Nítrico/metabolismo
Espécies Reativas de Oxigênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Reactive Oxygen Species); 22150-76-1 (Biopterin); 31C4KY9ESH (Nitric Oxide); EC 1.14.13.39 (Nitric Oxide Synthase Type III); EC 3.5.4.16 (GTP Cyclohydrolase); EC 3.5.4.16 (Gch1 protein, mouse); EGX657432I (sapropterin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170128
[St] Status:MEDLINE
[do] DOI:10.1111/bph.13728


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[PMID]:28114584
[Au] Autor:Edgar KS; Galvin OM; Collins A; Katusic ZS; McDonald DM
[Ad] Endereço:Centre for Experimental Medicine, Queen's University Belfast, United Kingdom.
[Ti] Título:BH4-Mediated Enhancement of Endothelial Nitric Oxide Synthase Activity Reduces Hyperoxia-Induced Endothelial Damage and Preserves Vascular Integrity in the Neonate.
[So] Source:Invest Ophthalmol Vis Sci;58(1):230-241, 2017 Jan 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: Endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) has important vasoprotective functions that are compromised in the vasodegenerative phase of retinopathy of prematurity, owing to hyperoxia-induced depletion of the essential NOS cofactor BH4. Because modulating eNOS function can be beneficial or detrimental, our aim was to investigate the effect of BH4 supplementation on eNOS function and vascular regression in hyperoxia. Methods: Endothelial-specific eNOS-green fluorescent protein (GFP) overexpressing mice at postnatal day 7 (P7) were exposed to hyperoxia for 48 hours in the presence or absence of supplemental BH4, achieved by administration of sepiapterin, a stable BH4 precursor. Tissue was collected either for retinal flat mounts that were stained with lectin to determine the extent of vessel coverage or for analysis of BH4 by high-performance liquid chromatography, nitrotyrosine (NT) marker by Western blotting, VEGF expression by ELISA, and NOS activity by arginine-to-citrulline conversion. Primary retinal microvascular endothelial cells (RMEC) were similarly treated, and hyperoxia-induced damage was determined. Results: Sepiapterin effectively enhanced BH4 levels in hyperoxia-exposed retinas and brains, elevated NOS activity, and reduced NT-modified protein, leading to reversal of the exacerbated vasoregression observed in the presence of eNOS overexpression. In RMECs, hyperoxia-mediated depletion of BH4 dysregulated the redox balance by reducing nitrite and elevating superoxide and impaired proliferative ability. BH4 supplementation restored normal RMEC proliferation in vitro and also in vivo, providing a mechanistic link with the enhanced vascular coverage in eNOS-GFP retinas. Conclusions: These results demonstrate that BH4 supplementation corrects hyperoxia-induced RMEC dysfunction and preserves vascular integrity by enhancing eNOS function.
[Mh] Termos MeSH primário: Biopterina/análogos & derivados
Endotélio Vascular/enzimologia
Hiperóxia/prevenção & controle
Óxido Nítrico Sintase Tipo III/metabolismo
Vasos Retinianos/enzimologia
Retinopatia da Prematuridade/prevenção & controle
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Biopterina/farmacologia
Western Blotting
Células Cultivadas
Modelos Animais de Doenças
Endotélio Vascular/efeitos dos fármacos
Endotélio Vascular/patologia
Ensaio de Imunoadsorção Enzimática
Seres Humanos
Hiperóxia/complicações
Hiperóxia/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Óxido Nítrico Sintase Tipo III/efeitos dos fármacos
Vasos Retinianos/efeitos dos fármacos
Vasos Retinianos/patologia
Retinopatia da Prematuridade/etiologia
Retinopatia da Prematuridade/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
22150-76-1 (Biopterin); EC 1.14.13.39 (Nitric Oxide Synthase Type III); EGX657432I (sapropterin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170621
[Lr] Data última revisão:
170621
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170124
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.16-20523



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