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[PMID]:29215423
[Au] Autor:Anderson S
[Ad] Endereço:Sharon Anderson is an Assistant Professor, Rutgers School of Nursing, Newark, and Advanced Practice Nurse, Pediatric Genetics, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ. The author can be reached via e-mail at sharon.anderson@rutgers.edu.
[Ti] Título:GALT Deficiency Galactosemia.
[So] Source:MCN Am J Matern Child Nurs;43(1):44-51, 2018 Jan/Feb.
[Is] ISSN:1539-0683
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Galactosemia is an inborn error of galactose metabolism that results from a deficiency in one of three enzymes, uridine diphosphate galactose 4'epimerase, galactokinase, or galactose-1-phosphate uridyltransferase (GALT). This article focuses on classical, clinical variant, and biochemical variant (Duarte) galactosemias caused by GALT enzyme deficiency. A brief overview of galactosemia and newborn screening is presented, followed by detailed information about each of the conditions. Confirmatory testing, acute and long-term management, and outcome for these galactosemia types are discussed as well as the importance of genetic counseling and testing for the infant and family to refine reproductive risk.
[Mh] Termos MeSH primário: Galactosemias/diagnóstico
Galactosemias/fisiopatologia
Triagem Neonatal/métodos
UTP-Hexose-1-Fosfato Uridililtransferase/análise
[Mh] Termos MeSH secundário: Galactosemias/metabolismo
Seres Humanos
Recém-Nascido
Necessidades Nutricionais
UTP-Hexose-1-Fosfato Uridililtransferase/sangue
UTP-Hexose-1-Fosfato Uridililtransferase/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.7.10 (UTP-Hexose-1-Phosphate Uridylyltransferase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM; N
[Da] Data de entrada para processamento:171208
[St] Status:MEDLINE
[do] DOI:10.1097/NMC.0000000000000388


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[PMID]:28450132
[Au] Autor:De Lucca M; Barba C; Casique L
[Ad] Endereço:Laboratorio de Biología Molecular y Celular, Universidad Técnica de Ambato, Ambato, Ecuador. Electronic address: ma.delucca@uta.edu.ec.
[Ti] Título:A novel splicing mutation in GALT gene causing Galactosemia in Ecuadorian family.
[So] Source:Clin Chim Acta;470:20-23, 2017 Jul.
[Is] ISSN:1873-3492
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Classic Galactosemia (OMIM 230400) is an autosomal recessive disorder of galactose metabolism caused by mutations in the galactose-1-phosphate uridyl transferase (GALT) gene. This disease caused by the inability to metabolize galactose is potentially life-threatening but its pathophysiology has not been clearly defined. GALT gene presents high allelic heterogeneity and around 336 variations have been identified. Here, we report the case of a patient with Classic Galactosemia who was detected during a neonatal screening in Ecuador. Molecular study revealed a mutation in GALT gene intron 1, c.82+3A>G in homozygous condition, this mutation has not been previously reported. This gene variation was not found in any of the 119 healthy Ecuadorian individuals used as control. Furthermore, the mutation was the only alteration detected in the propositus's GALT after sequencing all exons and introns of this gene. In silico modeling predicted that the mutation was pathogenic.
[Mh] Termos MeSH primário: Galactosemias/enzimologia
Galactosemias/genética
Mutação
Linhagem
Processamento de RNA/genética
UTP-Hexose-1-Fosfato Uridililtransferase/genética
[Mh] Termos MeSH secundário: Adulto
Sequência de Bases
Pré-Escolar
Biologia Computacional
Equador
Feminino
Homozigoto
Seres Humanos
Masculino
Polimorfismo de Nucleotídeo Único
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.7.10 (UTP-Hexose-1-Phosphate Uridylyltransferase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE


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[PMID]:28173647
[Au] Autor:Yang RL; Tong F; Hong F; Qian GL; Wu DW; Zhao ZY
[Ad] Endereço:Department of Genetic and Metabolic diseases, Children's Hospital of Zhejiang University School of Medicine, Hangzhou 310052, China.
[Ti] Título:[Analysis of newborn screening for galactosemia and genotype-phenotype of confirmed galatosemia cases].
[So] Source:Zhonghua Er Ke Za Zhi;55(2):104-109, 2017 Feb 02.
[Is] ISSN:0578-1310
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:To investigate the prevalence of galactosemia(GAL), and the characteristics of genotype and phenotype of newborns who were confirmed with GAL in newborn screening in Zhejiang province. The number of all live births, newborn screened infants and all clinical data of confirmed newborns with GAL from October 2013 to March 2015 were retrospectively analyzed by reviewing the data of Zhejiang Province screening center database. And the characteristics of genes and the clinical data of GAL cases who were confirmed by correlative gene test and enzyme activity measurement were analyzed. The prevalence of GAL in Zhejiang province was 1/189 857. Among them, there was 1 case confirmed with GAL typeâ…  (prevalence, 1/759 428), with mutations of c. 904+ 1G>T and c. 687G>A, the enzyme activity of galactose-1-phosphate uridyltransferase (GALT) was 56.4% of controls. And there was 1 case of GAL typeâ…¡(prevalence, 1/759 428), with mutations of c. 85G>T and c. 502G>A. There were 2 cases confirmed with GAL type â…¢(prevalence, 1/379 714), with mutations of c. 505C>T, c. 452G>A, c. 280G>A and c. 925G>A, the enzyme activity of UDP-galactose-4'-epimerase (GALE) were 42% and 38% of controls, respectively. All cases had different abnormal biochemical marks of liver function, and 1 case had combined hyperlactacidemia or hyperammonemia or increase of multiple kinds of amino acids, respectively. The newborn of GAL type â…¡ had phacoscotasmus before treatment. All the cases were fed with lactose free milk powder, and all the abnormal parameters were improved during following up. The disease of GAL is rare in Zhejiang province, and its genotype distribution is scattered with comparatively mind clinical manifestations, and the cases with early treatment with lactose free milk powder have good prognosis. All cases needed to be treated and followed up for a life-long time. It is recommended that the high risk cases with GAL should be screened as soon as possible.
[Mh] Termos MeSH primário: Galactosemias/diagnóstico
Triagem Neonatal
[Mh] Termos MeSH secundário: Testes Genéticos
Genótipo
Seres Humanos
Lactente
Recém-Nascido
Mutação
Fenótipo
Prevalência
UDPglucose 4-Epimerase
UTP-Hexose-1-Fosfato Uridililtransferase
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.7.10 (UTP-Hexose-1-Phosphate Uridylyltransferase); EC 5.1.3.2 (UDPglucose 4-Epimerase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170727
[Lr] Data última revisão:
170727
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170209
[St] Status:MEDLINE
[do] DOI:10.3760/cma.j.issn.0578-1310.2017.02.010


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[PMID]:28075131
[Au] Autor:Staubach S; Müller S; Pekmez M; Hanisch FG
[Ad] Endereço:Institute of Biochemistry II, Medical Faculty, University of Cologne , Joseph-Stelzmann-Str. 52, 50931 Köln, Germany.
[Ti] Título:Classical Galactosemia: Insight into Molecular Pathomechanisms by Differential Membrane Proteomics of Fibroblasts under Galactose Stress.
[So] Source:J Proteome Res;16(2):516-527, 2017 Feb 03.
[Is] ISSN:1535-3907
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Classical galactosemia, a hereditary metabolic disease caused by the deficiency of galactose-1-phosphate uridyltransferase (GALT; EC 2.7.712), results in an impaired galactose metabolism and serious long-term developmental affection of the CNS and ovaries, potentially related in part to endogenous galactose-induced protein dysglycosylation. In search for galactose-induced changes in membrane raft proteomes of GALT-deficient cells, we performed differential analyses of lipid rafts from patient-derived (Q) and sex- and age-matched control fibroblasts (H) in the presence or absence of the stressor. Label-based proteomics revealed of the total 454 (female) or 678 (male) proteins a proportion of ∼12% in at least one of four relevant ratios as fold-changed. GALT(-) cell-specific effects in the absence of stressor revealed cell-model-dependent affection of biological processes related to protein targeting to the plasma membrane (female) or to cellular migration (male). However, a series of common galactose-induced effects were observed, among them the strongly increased ER-stress marker GRP78 and calreticulin involved in N-glycoprotein quality control. The membrane-anchored N-glycoprotein receptor CD109 was concertedly decreased under galactose-stress together with cadherin-13, GLIPR1, glypican-1, and semaphorin-7A. A series of proteins showed opposite fold-changes in the two cell models, whereas others fluctuated in only one of the two models.
[Mh] Termos MeSH primário: Fibroblastos/efeitos dos fármacos
Galactose/farmacologia
Galactosemias/genética
Regulação da Expressão Gênica/efeitos dos fármacos
Microdomínios da Membrana/efeitos dos fármacos
[Mh] Termos MeSH secundário: Antígenos CD/genética
Antígenos CD/metabolismo
Caderinas/genética
Caderinas/metabolismo
Calreticulina/genética
Calreticulina/metabolismo
Estudos de Casos e Controles
Pré-Escolar
Feminino
Fibroblastos/metabolismo
Fibroblastos/patologia
Proteínas Ligadas por GPI/genética
Proteínas Ligadas por GPI/metabolismo
Galactosemias/metabolismo
Galactosemias/patologia
Perfilação da Expressão Gênica
Ontologia Genética
Glipicanas/genética
Glipicanas/metabolismo
Proteínas de Choque Térmico/genética
Proteínas de Choque Térmico/metabolismo
Seres Humanos
Lactente
Masculino
Microdomínios da Membrana/química
Microdomínios da Membrana/metabolismo
Anotação de Sequência Molecular
Proteínas de Neoplasias/genética
Proteínas de Neoplasias/metabolismo
Proteínas do Tecido Nervoso/genética
Proteínas do Tecido Nervoso/metabolismo
Cultura Primária de Células
Semaforinas/genética
Semaforinas/metabolismo
Transdução de Sinais
Estresse Fisiológico
UTP-Hexose-1-Fosfato Uridililtransferase
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD); 0 (CD109 protein, human); 0 (Cadherins); 0 (Calreticulin); 0 (GLIPR1 protein, human); 0 (GPI-Linked Proteins); 0 (Glypicans); 0 (H-cadherin); 0 (Heat-Shock Proteins); 0 (Neoplasm Proteins); 0 (Nerve Tissue Proteins); 0 (SEMA7A protein, human); 0 (Semaphorins); 0 (calreticulin, human); 0 (molecular chaperone GRP78); EC 2.7.7.10 (UTP-Hexose-1-Phosphate Uridylyltransferase); X2RN3Q8DNE (Galactose)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170112
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jproteome.6b00658


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[PMID]:28065439
[Au] Autor:Welling L; Boelen A; Derks TG; Schielen PC; de Vries M; Williams M; Wijburg FA; Bosch AM
[Ad] Endereço:Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: lindsey.welling@amc.uva.nl.
[Ti] Título:Nine years of newborn screening for classical galactosemia in the Netherlands: Effectiveness of screening methods, and identification of patients with previously unreported phenotypes.
[So] Source:Mol Genet Metab;120(3):223-228, 2017 Mar.
[Is] ISSN:1096-7206
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Newborn screening (NBS) for classical galactosemia (CG) was introduced in the Netherlands in 2007. Multiple screening methods have been used since, and currently a two-tier system is used, with residual enzyme activity of galactose-1-phosphate-uridyltransferase (GALT) and total galactose concentration in dried blood spots as the primary and secondary markers. As it is essential to monitor effectiveness of NBS programs, we assessed the effectiveness of different screening methods used over time (primary aim), and aimed to identify and investigate patients identified through NBS with previously unreported clinical and biochemical phenotypes (secondary aim). METHODS: The effectiveness of different screening methods and their cut-off values (COVs), as used from 2007 through 2015, was determined, and the clinical and biochemical data of all identified patients were retrospectively collected. RESULTS: All screening methods and COVs resulted in relatively high false-positive rates and low positive predictive values. Total galactose levels in dried blood spots were far above the COV for NBS in all true positive cases. A total of 31 galactosemia patients were identified, and when corrected for a family with three affected siblings, 14% had a previously unreported phenotype and genotype. These individuals did not demonstrate any symptoms at the time of diagnosis while still being exposed to galactose, had galactose-1-phosphate values below detection limit within months after the start of diet, and had previously unreported genotypes. CONCLUSION: Optimization of NBS for CG in the Netherlands is warranted because of the high false-positive rate, which may result in significant harm. Furthermore, a surprising 14% of newborns identified with CG by screening had previously unreported clinical and biochemical phenotypes and genotypes. For them, individualized prognostication and treatment are warranted, in order to avoid unnecessary stringent galactose restriction.
[Mh] Termos MeSH primário: Galactose/sangue
Galactosemias/diagnóstico
Triagem Neonatal/métodos
UTP-Hexose-1-Fosfato Uridililtransferase/metabolismo
[Mh] Termos MeSH secundário: Reações Falso-Positivas
Feminino
Galactosemias/genética
Galactosemias/metabolismo
Seres Humanos
Recém-Nascido
Masculino
Países Baixos
Fenótipo
Estudos Retrospectivos
Sensibilidade e Especificidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.7.10 (UTP-Hexose-1-Phosphate Uridylyltransferase); X2RN3Q8DNE (Galactose)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170829
[Lr] Data última revisão:
170829
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170110
[St] Status:MEDLINE


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[PMID]:27919945
[Au] Autor:Tang M; Etokidem E; Lai K
[Ad] Endereço:Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, U.S.A. manshu.tang@hsc.utah.edu kent.lai@hsc.utah.edu.
[Ti] Título:The Leloir Pathway of Galactose Metabolism - A Novel Therapeutic Target for Hepatocellular Carcinoma.
[So] Source:Anticancer Res;36(12):6265-6271, 2016 12.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:Hepatocellular carcinoma (HCC) is one of the most lethal types of cancer worldwide, with poor prognosis and limited treatments. In order to identify novel therapeutic targets that will lead to development of effective therapies with manageable side effects, we tested the hypothesis that knocking-down galactokinase (GALK1) or galactose-1 phosphate uridylyltransferase (GALT) gene expression would control the growth of cultured hepatoma cells. Our results showed small interfering RNA (siRNA) against GALK1 or GALT inhibited the growth of HepG2 cells in culture. Western blot analysis revealed simultaneous down-regulation of multiple players of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) growth signaling pathway, as well as heat-shock protein 90 (HSP90) and poly ADP ribose polymerase (PARP). Reverse transcription-polymerase chain reaction (RT-PCR) data, however, showed no significant mRNA reduction of the encoded genes. Our study thus not only supports GALK1 and GALT as being possible novel targets for treating HCC, but also uncovers new post-transcriptional regulatory mechanisms that link the galactose metabolic pathway to protein expression of the PI3K/AKT pathway in hepatoma.
[Mh] Termos MeSH primário: Carcinoma Hepatocelular/metabolismo
Galactose/metabolismo
Neoplasias Hepáticas/terapia
[Mh] Termos MeSH secundário: Carcinoma Hepatocelular/terapia
Galactoquinase/genética
Galactoquinase/metabolismo
Células Hep G2
Seres Humanos
Neoplasias Hepáticas/metabolismo
RNA Interferente Pequeno
UTP-Hexose-1-Fosfato Uridililtransferase/genética
UTP-Hexose-1-Fosfato Uridililtransferase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Small Interfering); EC 2.7.1.6 (GALK1 protein, human); EC 2.7.1.6 (Galactokinase); EC 2.7.7.10 (UTP-Hexose-1-Phosphate Uridylyltransferase); X2RN3Q8DNE (Galactose)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170830
[Lr] Data última revisão:
170830
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161207
[St] Status:MEDLINE


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[PMID]:27466186
[Au] Autor:Jumbo-Lucioni PP; Parkinson WM; Kopke DL; Broadie K
[Ad] Endereço:Department of Biological Sciences.
[Ti] Título:Coordinated movement, neuromuscular synaptogenesis and trans-synaptic signaling defects in Drosophila galactosemia models.
[So] Source:Hum Mol Genet;25(17):3699-3714, 2016 Sep 01.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The multiple galactosemia disease states manifest long-term neurological symptoms. Galactosemia I results from loss of galactose-1-phosphate uridyltransferase (GALT), which converts galactose-1-phosphate + UDP-glucose to glucose-1-phosphate + UDP-galactose. Galactosemia II results from loss of galactokinase (GALK), phosphorylating galactose to galactose-1-phosphate. Galactosemia III results from the loss of UDP-galactose 4'-epimerase (GALE), which interconverts UDP-galactose and UDP-glucose, as well as UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine. UDP-glucose pyrophosphorylase (UGP) alternatively makes UDP-galactose from uridine triphosphate and galactose-1-phosphate. All four UDP-sugars are essential donors for glycoprotein biosynthesis with critical roles at the developing neuromuscular synapse. Drosophila galactosemia I (dGALT) and II (dGALK) disease models genetically interact; manifesting deficits in coordinated movement, neuromuscular junction (NMJ) development, synaptic glycosylation, and Wnt trans-synaptic signalling. Similarly, dGALE and dUGP mutants display striking locomotor and NMJ formation defects, including expanded synaptic arbours, glycosylation losses, and differential changes in Wnt trans-synaptic signalling. In combination with dGALT loss, both dGALE and dUGP mutants compromise the synaptomatrix glycan environment that regulates Wnt trans-synaptic signalling that drives 1) presynaptic Futsch/MAP1b microtubule dynamics and 2) postsynaptic Frizzled nuclear import (FNI). Taken together, these findings indicate UDP-sugar balance is a key modifier of neurological outcomes in all three interacting galactosemia disease models, suggest that Futsch homolog MAP1B and the Wnt Frizzled receptor may be disease-relevant targets in epimerase and transferase galactosemias, and identify UGP as promising new potential therapeutic target for galactosemia neuropathology.
[Mh] Termos MeSH primário: Galactoquinase/genética
Galactosemias/fisiopatologia
Junção Neuromuscular/patologia
Sinapses/fisiologia
UTP-Hexose-1-Fosfato Uridililtransferase/genética
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Drosophila
Proteínas de Drosophila/genética
Galactosemias/metabolismo
Galactosemias/patologia
Glicosilação
Seres Humanos
Junção Neuromuscular/metabolismo
Sinapses/metabolismo
Via de Sinalização Wnt
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drosophila Proteins); EC 2.7.1.6 (Galactokinase); EC 2.7.7.10 (UTP-Hexose-1-Phosphate Uridylyltransferase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170902
[Lr] Data última revisão:
170902
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160729
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddw217


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Porta, Gilda
PubMed Central Texto completo
Texto completo
[PMID]:27176039
[Au] Autor:Garcia DF; Camelo JS; Molfetta GA; Turcato M; Souza CF; Porta G; Steiner CE; Silva WA
[Ad] Endereço:Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
[Ti] Título:Clinical profile and molecular characterization of Galactosemia in Brazil: identification of seven novel mutations.
[So] Source:BMC Med Genet;17(1):39, 2016 May 12.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Classical Galactosemia (CG) is an inborn error of galactose metabolism caused by the deficiency of the galactose-1-phosphate uridyltransferase enzyme. It is transmitted as an autosomal recessive disease and is typically characterized by neonatal galactose intolerance, with complications ranging from neonatal jaundice and liver failure to late complications, such as motor and reproductive dysfunctions. Galactosemia is also heterogeneous from a molecular standpoint, with hundreds of different mutations described in the GALT gene, some of them specific to certain populations, reflecting consequence of founder effect. METHODS: This study reviews the main clinical findings and depicts the spectrum of mutations identified in 19 patients with CG, six with Duarte Galactosemia and one with type 2 Galactosemia in Brazil. Some individuals were diagnosed through expanded newborn screening test, which is not available routinely to all newborns. RESULTS: The main classical Galactosemia mutations reported to date were identified in this study, as well as the Duarte variant and seven novel mutations - c.2 T > C (p.M1T), c.97C > A (p.R33S), c.217C > T (p.P73S), c.328 + 1G > A (IVS3 + 1G > A), c.377 + 4A > C (IVS4 + 4A > C), c.287_289delACA (p.N97del) and c.506A > C (p.Q169P). This was expected, given the high miscegenation of the Brazilian population. CONCLUSIONS: This study expands the mutation spectrum in GALT gene and reinforces the importance of early diagnosis and introduction of dietary treatment, what is possible with the introduction of Galactosemia in neonatal screening programs.
[Mh] Termos MeSH primário: Galactosemias/genética
Galactosemias/patologia
Mutação
UTP-Hexose-1-Fosfato Uridililtransferase/genética
[Mh] Termos MeSH secundário: Alelos
Sequência de Bases
Brasil
DNA/química
DNA/isolamento & purificação
DNA/metabolismo
Genótipo
Seres Humanos
Lactente
Recém-Nascido
Polimorfismo Genético
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
9007-49-2 (DNA); EC 2.7.7.10 (UTP-Hexose-1-Phosphate Uridylyltransferase)
[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:160514
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-016-0300-8


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[PMID]:27005423
[Au] Autor:McCorvie TJ; Kopec J; Pey AL; Fitzpatrick F; Patel D; Chalk R; Shrestha L; Yue WW
[Ad] Endereço:Structural Genomics Consortium, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7DQ , UK.
[Ti] Título:Molecular basis of classic galactosemia from the structure of human galactose 1-phosphate uridylyltransferase.
[So] Source:Hum Mol Genet;25(11):2234-2244, 2016 Jun 01.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Classic galactosemia is a potentially lethal disease caused by the dysfunction of galactose 1-phosphate uridylyltransferase (GALT). Over 300 disease-associated GALT mutations have been reported, with the majority being missense changes, although a better understanding of their underlying molecular effects has been hindered by the lack of structural information for the human enzyme. Here, we present the 1.9 Å resolution crystal structure of human GALT (hGALT) ternary complex, revealing a homodimer arrangement that contains a covalent uridylylated intermediate and glucose-1-phosphate in the active site, as well as a structural zinc-binding site, per monomer. hGALT reveals significant structural differences from bacterial GALT homologues in metal ligation and dimer interactions, and therefore is a zbetter model for understanding the molecular consequences of disease mutations. Both uridylylation and zinc binding influence the stability and aggregation tendency of hGALT. This has implications for disease-associated variants where p.Gln188Arg, the most commonly detected, increases the rate of aggregation in the absence of zinc likely due to its reduced ability to form the uridylylated intermediate. As such our structure serves as a template in the future design of pharmacological chaperone therapies and opens new concepts about the roles of metal binding and activity in protein misfolding by disease-associated mutants.
[Mh] Termos MeSH primário: Galactosemias/genética
Relação Estrutura-Atividade
Fatores de Complexo Ternário/química
UTP-Hexose-1-Fosfato Uridililtransferase/genética
[Mh] Termos MeSH secundário: Sítios de Ligação/genética
Domínio Catalítico/genética
Cristalografia por Raios X
Galactose/química
Galactose/metabolismo
Galactosemias/metabolismo
Galactosemias/patologia
Seres Humanos
Cinética
Modelos Moleculares
Mutagênese Sítio-Dirigida
Mutação
Conformação Proteica
Fatores de Complexo Ternário/genética
UTP-Hexose-1-Fosfato Uridililtransferase/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ternary Complex Factors); EC 2.7.7.10 (UTP-Hexose-1-Phosphate Uridylyltransferase); X2RN3Q8DNE (Galactose)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160324
[St] Status:MEDLINE


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[PMID]:26773505
[Au] Autor:Balakrishnan B; Chen W; Tang M; Huang X; Cakici DD; Siddiqi A; Berry G; Lai K
[Ad] Endereço:Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, USA.
[Ti] Título:Galactose-1 phosphate uridylyltransferase (GalT) gene: A novel positive regulator of the PI3K/Akt signaling pathway in mouse fibroblasts.
[So] Source:Biochem Biophys Res Commun;470(1):205-12, 2016 Jan 29.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The vital importance of the Leloir pathway of galactose metabolism has been repeatedly demonstrated by various uni-/multicellular model organisms, as well human patients who have inherited deficiencies of the key GAL enzymes. Yet, other than the obvious links to the glycolytic pathway and glycan biosynthetic pathways, little is known about how this metabolic pathway interacts with the rest of the metabolic and signaling networks. In this study, we compared the growth and the expression levels of the key components of the PI3K/Akt growth signaling pathway in primary fibroblasts derived from normal and galactose-1 phosphate uridylyltransferase (GalT)-deficient mice, the latter exhibited a subfertility phenotype in adult females and growth restriction in both sexes. The growth potential and the protein levels of the pAkt(Thr308), pAkt(Ser473), pan-Akt, pPdk1, and Hsp90 proteins were significantly reduced by 62.5%, 60.3%, 66%, 66%, and 50%, respectively in the GalT-deficient cells. Reduced expression of phosphorylated Akt proteins in the mutant cells led to diminished phosphorylation of Gsk-3ß (-74%). Protein expression of BiP and pPten were 276% and 176% higher respectively in cells with GalT-deficiency. Of the 24 genes interrogated using QIAGEN RT(2) Profiler PCR Custom Arrays, the mRNA abundance of Akt1, Pdpk1, Hsp90aa1 and Pi3kca genes were significantly reduced at least 2.03-, 1.37-, 2.45-, and 1.78-fold respectively in mutant fibroblasts. Both serum-fasted normal and GalT-deficient cells responded to Igf-1-induced activation of Akt phosphorylation at +15 min, but the mutant cells have lower phosphorylation levels. The steady-state protein abundance of Igf-1 receptor was also significantly reduced in mutant cells. Our results thus demonstrated that GalT deficiency can effect down-regulation of the PI3K/Akt growth signaling pathway in mouse fibroblasts through distinct mechanisms targeting both gene and protein expression levels.
[Mh] Termos MeSH primário: Fibroblastos/metabolismo
Galactosemias/metabolismo
Fosfatidilinositol 3-Quinases/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Transdução de Sinais/fisiologia
UTP-Hexose-1-Fosfato Uridililtransferase/metabolismo
[Mh] Termos MeSH secundário: Animais
Estresse do Retículo Endoplasmático
Feminino
Galactosemias/patologia
Regulação Enzimológica da Expressão Gênica
Masculino
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.7.10 (UTP-Hexose-1-Phosphate Uridylyltransferase)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:170129
[Lr] Data última revisão:
170129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160117
[St] Status:MEDLINE



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