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[PMID]: 28982351 [Au] Autor: Liu N; Huang Q; Li Q; Zhao D; Li X; Cui L; Bai Y; Feng Y; Kong X [Ad] Endereço: Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University, Henan Engineering Research Center for Gene Editing of Human Genetic Disease, Jianshe Rd, Erqi District, Zhengzhou, Henan, 450052, People's Republic of China. [Ti] Título: Spectrum of PAH gene variants among a population of Han Chinese patients with phenylketonuria from northern China. [So] Source: BMC Med Genet;18(1):108, 2017 Oct 05. [Is] ISSN: 1471-2350 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: BACKGROUND: Phenylketonuria (PKU), which primarily results from a deficiency of phenylalanine hydroxylase (PAH), is one of the most common inherited inborn errors of metabolism that impairs postnatal cognitive development. The incidence of various PAH variations differs by race and ethnicity. The aim of the present study was to characterize the PAH gene variants of a Han population from Northern China. METHODS: In total, 655 PKU patients and their families were recruited for this study; each proband was diagnosed both clinically and biochemically with phenylketonuria. Subjects were sequentially screened for single-base variants and exon deletions or duplications within PAH via direct Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). RESULTS: A spectrum of 174 distinct PAH variants was identified: 152 previously documented variants and 22 novel variants. While single-base variants were distributed throughout the 13 exons, they were particularly concentrated in exons 7 (33.3%), 11 (14.2%), 6 (13.2%), 12 (11.0%), 3 (10.4%), and 5 (4.4%). The predominant variant was p.Arg243Gln (17.7%), followed by Ex6-96A > G (8.3%), p.Val399 = (6.4%), p.Arg53His (4.7%), p.Tyr356* (4.7%), p.Arg241Cys (4.6%), p.Arg413Pro (4.6%), p.Arg111* (4.4%), and c.442-1G > A (3.4%). Notably, two patients were also identified as carrying de novo variants. CONCLUSION: The composition of PAH gene variants in this Han population from Northern China was distinct from those of other ethnic groups. As such, the construction of a PAH gene variant database for Northern China is necessary to lay a foundation for genetic-based diagnoses, prenatal diagnoses, and population screening. [Mh] Termos MeSH primário: Grupo com Ancestrais do Continente Asiático/genética Variação Genética Fenilalanina Hidroxilase/genética Fenilcetonúrias/diagnóstico Fenilcetonúrias/genética [Mh] Termos MeSH secundário: Pré-Escolar China Variações do Número de Cópias de DNA Éxons Estudos de Associação Genética Seres Humanos Lactente Reação em Cadeia da Polimerase Multiplex Diagnóstico Pré-Natal Reprodutibilidade dos Testes [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: EC 1.14.16.1 (Phenylalanine Hydroxylase) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171017 [Lr] Data última revisão: 171017 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171007 [St] Status: MEDLINE [do] DOI: 10.1186/s12881-017-0467-7

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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

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[PMID]: 28850618 [Au] Autor: Fiori E; Oddi D; Ventura R; Colamartino M; Valzania A; D'Amato FR; Bruinenberg V; van der Zee E; Puglisi-Allegra S; Pascucci T [Ad] Endereço: Department of Psychology and Centro "Daniel Bovet", Sapienza University, Rome, Italy. [Ti] Título: Early-onset behavioral and neurochemical deficits in the genetic mouse model of phenylketonuria. [So] Source: PLoS One;12(8):e0183430, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Phenylketonuria (PKU) is one of the most common human inborn errors of metabolism, caused by phenylalanine hydroxylase deficiency, leading to high phenylalanine and low tyrosine levels in blood and brain causing profound cognitive disability, if untreated. Since 1960, population is screened for hyperphenylalaninemia shortly after birth and submitted to early treatment in order to prevent the major manifestations of the disease. However, the dietetic regimen (phenylalanine free diet) is difficult to maintain, and despite the recommendation to a strict and lifelong compliance, up to 60% of adolescents partially or totally abandons the treatment. The development and the study of new treatments continue to be sought, taking advantage of preclinical models, the most used of which is the PAHenu2 (BTBR ENU2), the genetic murine model of PKU. To date, adult behavioral and neurochemical alterations have been mainly investigated in ENU2 mice, whereas there are no clear indications about the onset of these deficiencies. Here we investigated and report, for the first time, a comprehensive behavioral and neurochemical assay of the developing ENU2 mice. Overall, our findings demonstrate that ENU2 mice are significantly smaller than WT until pnd 24, present a significant delay in the acquisition of tested developmental reflexes, impaired communicative, motor and social skills, and have early reduced biogenic amine levels in several brain areas. Our results extend the understanding of behavioral and cerebral abnormalities in PKU mice, providing instruments to an early preclinical evaluation of the effects of new treatments. [Mh] Termos MeSH primário: Comportamento Animal/fisiologia Encéfalo/metabolismo Dopamina/metabolismo Norepinefrina/metabolismo Fenilcetonúrias/metabolismo Fenilcetonúrias/psicologia Serotonina/metabolismo [Mh] Termos MeSH secundário: Animais Modelos Animais de Doenças Camundongos Atividade Motora/fisiologia Fenilalanina Hidroxilase/genética Fenilcetonúrias/genética Reflexo/fisiologia Comportamento Social Vocalização Animal/fisiologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 333DO1RDJY (Serotonin); EC 1.14.16.1 (Phenylalanine Hydroxylase); VTD58H1Z2X (Dopamine); X4W3ENH1CV (Norepinephrine) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171019 [Lr] Data última revisão: 171019 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170830 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0183430

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[PMID]: 28697448 [Au] Autor: Hayakawa D; Yamaotsu N; Nakagome I; Ozawa SI; Yoshida T; Hirono S [Ad] Endereço: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address: hayakawad@pharm.kitasato-u.ac.jp. [Ti] Título: In silico analyses of the effects of a point mutation and a pharmacological chaperone on the thermal fluctuation of phenylalanine hydroxylase. [So] Source: Biophys Chem;228:47-54, 2017 Sep. [Is] ISSN: 1873-4200 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Phenylketonuria (PKU) is an inborn error of phenylalanine metabolism due to mutations in phenylalanine hydroxylase (PAH). Recently, small compounds, known as pharmacological chaperones (PhCs), have been identified that restore the enzymatic activity of mutant PAHs. Understanding the mechanism of the reduction in enzymatic activity due to a point mutation in PAH and its restoration by PhC binding is important for the design of more effective PhC drugs. Thermal fluctuations of an enzyme can alter its activity. Here, molecular dynamics simulation show the thermal fluctuation of PAH is increased by introduction of the A313T mutation. Moreover, a simulation using the A313T-PhC complex model was also performed. Thermal fluctuation of the mutant was found to be reduced upon PhC binding, which contributes to restoring its enzymatic activity. [Mh] Termos MeSH primário: Fenilalanina Hidroxilase/metabolismo [Mh] Termos MeSH secundário: Sítios de Ligação Domínio Catalítico Cristalografia por Raios X Simulação de Dinâmica Molecular Fenilalanina Hidroxilase/química Fenilalanina Hidroxilase/genética Mutação Puntual Dobramento de Proteína Pirimidinonas/química Pirimidinonas/metabolismo Temperatura Ambiente [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Pyrimidinones); 0 (thieno(2,3-d)pyrimidin-4-one); EC 1.14.16.1 (Phenylalanine Hydroxylase) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170817 [Lr] Data última revisão: 170817 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170712 [St] Status: 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

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[PMID]: 28604955 [Au] Autor: Li H; Li Y; Zhang L [Ad] Endereço: Genetic Laboratory, Women and Children's Health Care Hospital of Linyi, Linyi, Shandong 276014, China. lylihuafeng@163.com. [Ti] Título: [Characteristics of phenylalanine hydroxylase gene mutations among patients with phenylketonuria from Linyi region of Shandong Province]. [So] Source: Zhonghua Yi Xue Yi Chuan Xue Za Zhi;34(3):361-364, 2017 Jun 10. [Is] ISSN: 1003-9406 [Cp] País de publicação: China [La] Idioma: chi [Ab] Resumo: OBJECTIVE: To explore the characteristics of (PAH) gene mutations among patients with phenylketonuria (PKU) from Linyi area of Shandong Province. METHODS: For 51 children affected with PKU and their parents, the 13 exons and their flanking intronic sequences of the PAH gene were directly sequenced with Sanger method. RESULTS: PAH gene mutations were detected in all of the 102 alleles of the patients, which included 31 types of mutations. Common mutations included R243Q (17/102, 16.67%), IVS4-1G to A (9/102, 8.82%), R241C (8/102, 7.84%), R111X (8/102, 7.84%), and V399V (8/102, 7.84%). In addition, two novel mutations, D101N, 345-347del, have been detected. The 31 types of mutations included missense, nonsense, deletion, and splicing mutations, which were mainly located in exons 7 (29, 28.43%), 11 (18, 17.65%), 3 (16, 15.69%) and 12 (13, 12.75%). CONCLUSION: Mutations of the PAH gene in Linyi region mainly distributed in exons 7, 11, and 3, and the most common mutation were R243Q. Two novel mutations, D101N and 345-347del, have been detected. [Mh] Termos MeSH primário: Mutação Fenilalanina Hidroxilase/genética Fenilcetonúrias/enzimologia Fenilcetonúrias/genética [Mh] Termos MeSH secundário: Sequência de Bases Criança Pré-Escolar China Éxons Feminino Seres Humanos Lactente Masculino Dados de Sequência Molecular [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: EC 1.14.16.1 (Phenylalanine Hydroxylase) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170914 [Lr] Data última revisão: 170914 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170613 [St] Status: MEDLINE [do] DOI: 10.3760/cma.j.issn.1003-9406.2017.03.010

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[PMID]: 28389235 [Au] Autor: Item CB; Farhadi S; Schanzer A; Greber-Platzer S [Ad] Endereço: Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, Austria. Electronic address: bellarmine.item@meduniwien.ac.at. [Ti] Título: DNA methylated alleles of the phenylalanine hydroxylase promoter remodeled at elevated phenylalanine levels in newborns with hyperphenylalaninemia. [So] Source: Clin Biochem;50(12):729-732, 2017 Aug. [Is] ISSN: 1873-2933 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: OBJECTIVES: Although high phenylalanine (phe) exposure has been shown to influence the DNA methylation status of leukocytes in hyperphenylalaninemia (HPA), the potential of DNA methylation changes as a biomarker of pretreatment high phe exposure in diet free newborns with HPA has not been explored. We therefore investigated the DNA methylation pattern of the phenylalanine hydroxylase (PAH) gene promoter at different phe levels, and the possibility of DNA methylation pattern changes being a biomarker of high phe exposure in diet free newborns with HPA. DESIGN AND METHODS: With a combination of methylated PCR, high resolution melting, and sequencing, the cytosine phosphodiester bond guanine (CpG) dinucleotides in the 5' untranslated region of the PAH gene were analysed 2-15days after birth using leukocyte DNA from diet free 16 newborns with HPA and 16 healthy controls. RESULTS: In 2-3days blood cards, GTGTG and GTGC/TG alleles were both detected at similar low mean phe levels in healthy controls (59.39±14.62 and 55.33±13.43µmol/L) and non-phenylketonuria (PKU) HPA (265.00 and 244.25±73.73µmol/L). In HPA with PKU, the GTGTG and GTGC/TG alleles were both detected at dissimilar elevated mean phe levels (380.80±64.62 and 589.00±191.96µmol/L). In ≥7day blood cards, GTGTG and GTGC/TG alleles were both detected at similar excess mean phe levels in HPA with PKU (2297±374.38 and 1562.66±718.23µmol/L). CONCLUSION: The demethylated GTGTG and partial methylated GTGC/TG alleles are not pathogenic alleles. Our results suggest a specific remodeling of the DNA methylated alleles of the PAH promoter at elevated, but not excess phe levels in diet free newborns with PKU. [Mh] Termos MeSH primário: Alelos Metilação de DNA Fenilalanina Hidroxilase/genética Fenilalanina/sangue Fenilcetonúrias/genética Regiões Promotoras Genéticas [Mh] Termos MeSH secundário: Regiões 5' não Traduzidas Estudos de Casos e Controles Ilhas de CpG Feminino Seres Humanos Recém-Nascido Masculino Desnaturação de Ácido Nucleico Fenilalanina Hidroxilase/sangue Fenilcetonúrias/sangue Fenilcetonúrias/diagnóstico Fenilcetonúrias/patologia Reação em Cadeia da Polimerase Análise de Sequência de DNA [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (5' Untranslated Regions); 47E5O17Y3R (Phenylalanine); EC 1.14.16.1 (Phenylalanine Hydroxylase) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170717 [Lr] Data última revisão: 170717 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170409 [St] Status: 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]: 27447460 [Au] Autor: Klaassen K; Stankovic B; Kotur N; Djordjevic M; Zukic B; Nikcevic G; Ugrin M; Spasovski V; Srzentic S; Pavlovic S; Stojiljkovic M [Ad] Endereço: Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11010, Belgrade, Serbia. [Ti] Título: New PAH gene promoter KLF1 and 3'-region C/EBPalpha motifs influence transcription in vitro. [So] Source: J Appl Genet;58(1):79-85, 2017 Feb. [Is] ISSN: 2190-3883 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Phenylketonuria (PKU) is a metabolic disease caused by mutations in the phenylalanine hydroxylase (PAH) gene. Although the PAH genotype remains the main determinant of PKU phenotype severity, genotype-phenotype inconsistencies have been reported. In this study, we focused on unanalysed sequences in non-coding PAH gene regions to assess their possible influence on the PKU phenotype. We transiently transfected HepG2 cells with various chloramphenicol acetyl transferase (CAT) reporter constructs which included PAH gene non-coding regions. Selected non-coding regions were indicated by in silico prediction to contain transcription factor binding sites. Furthermore, electrophoretic mobility shift assay (EMSA) and supershift assays were performed to identify which transcriptional factors were engaged in the interaction. We found novel KLF1 motif in the PAH promoter, which decreases CAT activity by 50 % in comparison to basal transcription in vitro. The cytosine at the c.-170 promoter position creates an additional binding site for the protein complex involving KLF1 transcription factor. Moreover, we assessed for the first time the role of a multivariant variable number tandem repeat (VNTR) region located in the 3'-region of the PAH gene. We found that the VNTR3, VNTR7 and VNTR8 constructs had approximately 60 % of CAT activity. The regulation is mediated by the C/EBPalpha transcription factor, present in protein complex binding to VNTR3. Our study highlighted two novel promoter KLF1 and 3'-region C/EBPalpha motifs in the PAH gene which decrease transcription in vitro and, thus, could be considered as PAH expression modifiers. New transcription motifs in non-coding regions will contribute to better understanding of the PKU phenotype complexity and may become important for the optimisation of PKU treatment. [Mh] Termos MeSH primário: Proteínas Estimuladoras de Ligação a CCAAT/metabolismo Fatores de Transcrição Kruppel-Like/metabolismo Fenilalanina Hidroxilase/genética Regiões Promotoras Genéticas Transcrição Genética [Mh] Termos MeSH secundário: Genótipo Células Hep G2 Seres Humanos Íntrons Repetições Minissatélites Fenótipo Fenilcetonúrias/genética Análise de Sequência de DNA [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (CCAAT-Enhancer-Binding Proteins); 0 (CEBPA protein, human); 0 (Kruppel-Like Transcription Factors); 0 (erythroid Kruppel-like factor); EC 1.14.16.1 (Phenylalanine Hydroxylase) [Em] Mês de entrada: 1702 [Cu] Atualização por classe: 171121 [Lr] Data última revisão: 171121 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160723 [St] Status: MEDLINE [do] DOI: 10.1007/s13353-016-0359-0

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[PMID]: 28853273 [Au] Autor: Ren G; Dong Z; Liu C; Liu Y; Luan Z; Liu Q; Bao X; Wang S [Ad] Endereço: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Liaoning Medical University, Jinzhou 121000, Liaoning, China. [Ti] Título: [The expression of phenylalanine hydroxylase in the brain of ragworm Neanthes japonica (Polychaeta, Annelida)]. [So] Source: Sheng Wu Gong Cheng Xue Bao;32(4):518-526, 2016 Apr 25. [Is] ISSN: 1000-3061 [Cp] País de publicação: China [La] Idioma: chi [Ab] Resumo: Phenylalanine hydroxylase (PAH) is a member of aromatic amino acid hydroxylase (AAAHs) family, and catalyze phenylalanine (Phe) into tyrosine (Tyr). Using immunological and RT-PCR methods to prove the existence of phenylalanine hydroxylase (PAH) gene in the brain of Neanthes japonica in protein and nucleic acid level. Using Western blotting to detect the pah immunogenicity of Neanthes japonica. Making paraffin sections and using immunohistochemical technique to identify the presence and distribution of the phenylalanine hydroxylase gene in the brain of Neanthes japonica. Clone pah gene from the brain of Neanthes japonica by RT-PCR, constructing plasmid and transferring into E. coli to amplification, picking a single homogeneous colony, double digesting then making sequence and comparing homology. Western blotting results showed that the expression of the protein is present in Neanthes japonica brain, immunohistochemistry technique results showed that phenylalanine hydroxylase mainly expressed in abdominal of forebrain, dorsal and sides of midbrain. RT-PCR technique results showed that the phenylalanine hydroxylase exist in the brain of Neanthes japonica and has a high homology with others animals. PAH is present in the lower organisms Neanthes japonica, in protein and nucleic acid level. Which provide the foundation for further study the evolution of aromatic amino acid hydroxylase genes in invertebrate. [Mh] Termos MeSH primário: Encéfalo/enzimologia Fenilalanina Hidroxilase/metabolismo Poliquetos/enzimologia [Mh] Termos MeSH secundário: Animais Western Blotting Escherichia coli/metabolismo Fenilalanina Hidroxilase/genética Poliquetos/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: EC 1.14.16.1 (Phenylalanine Hydroxylase) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171002 [Lr] Data última revisão: 171002 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170831 [St] Status: MEDLINE [do] DOI: 10.13345/j.cjb.150550

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