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[PMID]: 27774737 [Au] Autor: Yuste-Checa P; Brasil S; Gámez A; Underhaug J; Desviat LR; Ugarte M; Pérez-Cerdá C; Martinez A; Pérez B [Ad] Endereço: Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular-SO UAM-CSIC, Universidad Autónoma de Madrid, Campus de Cantoblanco, 28049 Madrid/Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Investigación Sanitaria IdiPAZ, Madrid, Spain. [Ti] Título: Pharmacological Chaperoning: A Potential Treatment for PMM2-CDG. [So] Source: Hum Mutat;38(2):160-168, 2017 Feb. [Is] ISSN: 1098-1004 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The congenital disorder of glycosylation (CDG) due to phosphomannomutase 2 deficiency (PMM2-CDG), the most common N-glycosylation disorder, is a multisystem disease for which no effective treatment is available. The recent functional characterization of disease-causing mutations described in patients with PMM2-CDG led to the idea of a therapeutic strategy involving pharmacological chaperones (PC) to rescue PMM2 loss-of-function mutations. The present work describes the high-throughput screening, by differential scanning fluorimetry, of 10,000 low-molecular-weight compounds from a commercial library, to search for possible PCs for the enzyme PMM2. This exercise identified eight compounds that increased the thermal stability of PMM2. Of these, four compounds functioned as potential PCs that significantly increased the stability of several destabilizing and oligomerization mutants and also increased PMM activity in a disease model of cells overexpressing PMM2 mutations. Structural analysis revealed one of these compounds to provide an excellent starting point for chemical optimization since it passed tests based on a number of pharmacochemical quality filters. The present results provide the first proof-of-concept of a possible treatment for PMM2-CDG and describe a promising chemical structure as a starting point for the development of new therapeutic agents for this severe orphan disease. [Mh] Termos MeSH primário: Defeitos Congênitos da Glicosilação/genética Fosfotransferases (Fosfomutases)/genética [Mh] Termos MeSH secundário: Alelos Defeitos Congênitos da Glicosilação/tratamento farmacológico Descoberta de Drogas Ativação Enzimática Fibroblastos/metabolismo Genótipo Ensaios de Triagem em Larga Escala Seres Humanos Mutação com Perda de Função Terapia de Alvo Molecular Mutação Fosfotransferases (Fosfomutases)/química Fosfotransferases (Fosfomutases)/isolamento & purificação Estabilidade Proteica Proteólise Proteínas Recombinantes de Fusão/química Proteínas Recombinantes de Fusão/genética Proteínas Recombinantes de Fusão/isolamento & purificação Proteínas Recombinantes de Fusão/metabolismo Bibliotecas de Moléculas Pequenas Relação Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Recombinant Fusion Proteins); 0 (Small Molecule Libraries); EC 5.4.2.- (Phosphotransferases (Phosphomutases)); EC 5.4.2.8 (phosphomannomutase 2, human) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180112 [Lr] Data última revisão: 180112 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161025 [St] Status: MEDLINE [do] DOI: 10.1002/humu.23138

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[PMID]: 29261720 [Au] Autor: Citro V; Cimmaruta C; Liguori L; Viscido G; Cubellis MV; Andreotti G [Ad] Endereço: Dipartimento di Biologia, Università Federico II, Napoli, Italy. [Ti] Título: A mutant of phosphomannomutase1 retains full enzymatic activity, but is not activated by IMP: Possible implications for the disease PMM2-CDG. [So] Source: PLoS One;12(12):e0189629, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The most frequent disorder of glycosylation, PMM2-CDG, is caused by a deficiency of phosphomannomutase activity. In humans two paralogous enzymes exist, both of them require mannose 1,6-bis-phosphate or glucose 1,6-bis-phosphate as activators, but only phospho-mannomutase1 hydrolyzes bis-phosphate hexoses. Mutations in the gene encoding phosphomannomutase2 are responsible for PMM2-CDG. Although not directly causative of the disease, the role of the paralogous enzyme in the disease should be clarified. Phosphomannomutase1 could have a beneficial effect, contributing to mannose 6-phosphate isomerization, or a detrimental effect, hydrolyzing the bis-phosphate hexose activator. A pivotal role in regulating mannose-1phosphate production and ultimately protein glycosylation might be played by inosine monophosphate that enhances the phosphatase activity of phosphomannomutase1. In this paper we analyzed human phosphomannomutases by conventional enzymatic assays as well as by novel techniques such as 31P-NMR and thermal shift assay. We characterized a triple mutant of phospomannomutase1 that retains mutase and phosphatase activity, but is unable to bind inosine monophosphate. [Mh] Termos MeSH primário: Defeitos Congênitos da Glicosilação/enzimologia Defeitos Congênitos da Glicosilação/genética Inosina Monofosfato/farmacologia Mutação/genética Fosfotransferases (Fosfomutases)/deficiência [Mh] Termos MeSH secundário: Sequência de Aminoácidos Difosfonatos/farmacologia Ativação Enzimática/efeitos dos fármacos Ensaios Enzimáticos Estabilidade Enzimática/efeitos dos fármacos Seres Humanos Ligantes Espectroscopia de Ressonância Magnética Simulação de Acoplamento Molecular Fosfotransferases (Fosfomutases)/química Fosfotransferases (Fosfomutases)/genética Alinhamento de Sequência Temperatura Ambiente [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Diphosphonates); 0 (Ligands); 131-99-7 (Inosine Monophosphate); EC 5.4.2.- (Phosphotransferases (Phosphomutases)); EC 5.4.2.8 (phosphomannomutase) [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: 171221 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0189629

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[PMID]: 28373276 [Au] Autor: Cabezas OR; Flanagan SE; Stanescu H; García-Martínez E; Caswell R; Lango-Allen H; Antón-Gamero M; Argente J; Bussell AM; Brandli A; Cheshire C; Crowne E; Dumitriu S; Drynda R; Hamilton-Shield JP; Hayes W; Hofherr A; Iancu D; Issler N; Jefferies C; Jones P; Johnson M; Kesselheim A; Klootwijk E; Koettgen M; Lewis W; Martos JM; Mozere M; Norman J; Patel V; Parrish A; Pérez-Cerdá C; Pozo J; Rahman SA; Sebire N; Tekman M; Turnpenny PD; Hoff WV; Viering DHHM; Weedon MN; Wilson P; Guay-Woodford L; Kleta R; Hussain K; Ellard S; Bockenhauer D [Ad] Endereço: Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain. [Ti] Título: Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2. [So] Source: J Am Soc Nephrol;28(8):2529-2539, 2017 08. [Is] ISSN: 1533-3450 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Hyperinsulinemic hypoglycemia (HI) and congenital polycystic kidney disease (PKD) are rare, genetically heterogeneous disorders. The co-occurrence of these disorders (HIPKD) in 17 children from 11 unrelated families suggested an unrecognized genetic disorder. Whole-genome linkage analysis in five informative families identified a single significant locus on chromosome 16p13.2 (logarithm of odds score 6.5). Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, we found in all patients a promoter mutation (c.-167G>T) in the phosphomannomutase 2 gene ( ), either homozygous or with coding mutations. encodes a key enzyme in N-glycosylation. Abnormal glycosylation has been associated with PKD, and we found that deglycosylation in cultured pancreatic cells altered insulin secretion. Recessive coding mutations in cause congenital disorder of glycosylation type 1a (CDG1A), a devastating multisystem disorder with prominent neurologic involvement. Yet our patients did not exhibit the typical clinical or diagnostic features of CDG1A. the promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. analysis suggested an important role of ZNF143 for the formation of a chromatin loop including We propose that the promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic causes for both HI and PKD and provide insights into gene regulation and pleiotropy. [Mh] Termos MeSH primário: Hiperinsulinismo Congênito/complicações Hiperinsulinismo Congênito/genética Mutação Fosfotransferases (Fosfomutases)/genética Doenças Renais Policísticas/complicações Doenças Renais Policísticas/genética Regiões Promotoras Genéticas/genética [Mh] Termos MeSH secundário: Pré-Escolar Feminino Seres Humanos Lactente Recém-Nascido Masculino [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: EC 5.4.2.- (Phosphotransferases (Phosphomutases)); EC 5.4.2.8 (phosphomannomutase 2, human) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170922 [Lr] Data última revisão: 170922 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170405 [St] Status: MEDLINE [do] DOI: 10.1681/ASN.2016121312

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[PMID]: 28112597 [Au] Autor: Patel HK; Ferrante P; Xianfa M; Javvadi SG; Subramoni S; Scortichini M; Venturi V [Ad] Endereço: First, third, fourth, fifth, and seventh authors: International Centre for Genetic Engineering and Biotechnology, Trieste, Italy; second and sixth authors: Research Centre for Fruit Crops, Agricultural Research Council, Roma, Italy; and sixth author: Research Unit for Fruit Trees, Council for Agricu [Ti] Título: Identification of Loci of Pseudomonas syringae pv. actinidiae Involved in Lipolytic Activity and Their Role in Colonization of Kiwifruit Leaves. [So] Source: Phytopathology;107(6):645-653, 2017 06. [Is] ISSN: 0031-949X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Bacterial canker disease caused by Pseudomonas syringae pv. actinidiae, an emerging pathogen of kiwifruit plants, has recently brought about major economic losses worldwide. Genetic studies on virulence functions of P. syringae pv. actinidiae have not yet been reported and there is little experimental data regarding bacterial genes involved in pathogenesis. In this study, we performed a genetic screen in order to identify transposon mutants altered in the lipolytic activity because it is known that mechanisms of regulation, production, and secretion of enzymes often play crucial roles in virulence of plant pathogens. We aimed to identify the set of secretion and global regulatory loci that control lipolytic activity and also play important roles in in planta fitness. Our screen for altered lipolytic activity phenotype identified a total of 58 Tn5 transposon mutants. Mapping all these Tn5 mutants revealed that the transposons were inserted in genes that play roles in cell division, chemotaxis, metabolism, movement, recombination, regulation, signal transduction, and transport as well as a few unknown functions. Several of these identified P. syringae pv. actinidiae Tn5 mutants, notably the functions affected in phosphomannomutase AlgC, lipid A biosynthesis acyltransferase, glutamate-cysteine ligase, and the type IV pilus protein PilI, were also found affected in in planta survival and/or growth in kiwifruit plants. The results of the genetic screen and identification of novel loci involved in in planta fitness of P. syringae pv. actinidiae are presented and discussed. [Mh] Termos MeSH primário: Actinidia/microbiologia Proteínas de Bactérias/genética Doenças das Plantas/microbiologia Pseudomonas syringae/genética [Mh] Termos MeSH secundário: Aciltransferases/genética Aciltransferases/metabolismo Proteínas de Bactérias/metabolismo Elementos de DNA Transponíveis Loci Gênicos/genética Glutamato-Cisteína Ligase/genética Glutamato-Cisteína Ligase/metabolismo Lipólise Mutagênese Insercional Fenótipo Fosfotransferases (Fosfomutases)/genética Fosfotransferases (Fosfomutases)/metabolismo Folhas de Planta/microbiologia Pseudomonas syringae/patogenicidade Pseudomonas syringae/fisiologia Virulência/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Bacterial Proteins); 0 (DNA Transposable Elements); EC 2.3.- (Acyltransferases); EC 5.4.2.- (Phosphotransferases (Phosphomutases)); EC 5.4.2.8 (phosphomannomutase); EC 6.3.2.2 (Glutamate-Cysteine Ligase) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170720 [Lr] Data última revisão: 170720 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170124 [St] Status: MEDLINE [do] DOI: 10.1094/PHYTO-10-16-0360-R

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[PMID]: 27415628 [Au] Autor: García-López R; de la Morena-Barrio ME; Alsina L; Pérez-Dueñas B; Jaeken J; Serrano M; Casado M; Hernández-Caselles T [Ad] Endereço: Departamento de Bioquímica, Biología Molecular B e Inmunología, Facultad de Medicina, IMIB-University of Murcia, Murcia, Spain. [Ti] Título: Natural Killer Cell Receptors and Cytotoxic Activity in Phosphomannomutase 2 Deficiency (PMM2-CDG). [So] Source: PLoS One;11(7):e0158863, 2016. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: BACKGROUND: PMM2-CDG is the most common N-glycosylation defect and shows an increased risk of recurrent and/or severe, sometimes fatal, infections in early life. We hypothesized that natural killer (NK) cells, as important mediators of the immune response against microbial pathogens and regulators of adaptive immunity, might be affected in this genetic disorder. OBJECTIVE: To evaluate possible defects on PMM2-CDG NK peripheral blood cell number, killing activity and expression of membrane receptors. METHODS: We studied fresh and activated NK cells from twelve PMM2-CDG cells. The number and expression of lymphoid surface receptors were studied by flow cytometry. The NK responsiveness (frequency of degranulated NK cells) and killing activity against K562 target cells was determined in the NK cytotoxicity assay. RESULTS: We found an increase of blood NK cells in three patients with a severe phenotype. Two of them, who had suffered from moderate/severe viral infections during their first year of life, also had reduced T lymphocyte numbers. Patient activated NK cells showed increased expression of CD54 adhesion molecule and NKG2D and NKp46 activating receptors. NKp46 and 2B4 expression was inversely correlated with the expression of NKG2D in activated PMM2-CDG cells. Maximal NK activity against K562 target cells was similar in control and PMM2-CDG cells. Interestingly, the NK cell responsiveness was higher in patient cells. NKG2D and specially CD54 increased surface expression significantly correlated with the increased NK cell cytolytic activity according to the modulation of the killer activity by expression of triggering receptors and adhesion molecules. CONCLUSIONS: Our results indicate that hypoglycosylation in PMM2-CDG altered NK cell reactivity against target cells and the expression of CD54 and NKG2D, NKp46 and 2B4 activating receptors during NK cell activation. This suggests a defective control of NK cell killing activity and the overall anti-viral immune response in PMM2-CDG patients. The present work improves our understanding of the immunological functions in PMM2-CDG and possibly in other CDG-I types. [Mh] Termos MeSH primário: Defeitos Congênitos da Glicosilação/metabolismo Fosfotransferases (Fosfomutases)/deficiência Receptores de Células Matadoras Naturais/metabolismo [Mh] Termos MeSH secundário: Adolescente Adulto Estudos de Casos e Controles Criança Pré-Escolar Defeitos Congênitos da Glicosilação/imunologia Testes Imunológicos de Citotoxicidade Feminino Citometria de Fluxo Seres Humanos Lactente Molécula 1 de Adesão Intercelular/metabolismo Células Matadoras Naturais/metabolismo Células Matadoras Naturais/fisiologia Ativação Linfocitária Masculino Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo Fosfotransferases (Fosfomutases)/imunologia Fosfotransferases (Fosfomutases)/metabolismo Adulto Jovem [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (KLRK1 protein, human); 0 (NCR1 protein, human); 0 (NK Cell Lectin-Like Receptor Subfamily K); 0 (Natural Cytotoxicity Triggering Receptor 1); 0 (Receptors, Natural Killer Cell); 126547-89-5 (Intercellular Adhesion Molecule-1); EC 5.4.2.- (Phosphotransferases (Phosphomutases)); EC 5.4.2.8 (phosphomannomutase 2, human) [Em] Mês de entrada: 1707 [Cu] Atualização por classe: 170720 [Lr] Data última revisão: 170720 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160715 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0158863

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[PMID]: 27314478 [Au] Autor: Qin HM; Li S; Zhang YF; Wang JW; Li J; Song S; Lu F; Li Y [Ad] Endereço: Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, No. 29 13th Avenue, Tianjin Economic and Technological Development Area, Tianjin, 300457, China. [Ti] Título: Multienzymatic cascade synthesis of fucosyloligosaccharide via a two-step fermentation strategy in Escherichia coli. [So] Source: Biotechnol Lett;38(10):1747-52, 2016 Oct. [Is] ISSN: 1573-6776 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: OBJECTIVES: To achieve multienzymatic cascade synthesis of fucosyl oligosaccharide from D-mannose by two-step fermentation pathway in Escherichia coli. RESULTS: E. coli BL21(DE3) harboring pET-22b(+) vectors with six genes, i.e., glucokinase (Glk), phosphomannomutase (ManB), mannose-1-phosphate guanylytransferase (ManC), GDP-mannose 4,6-dehydratase (Gmd), GDP-4-keto-6-deoxy-D-mannose-3,5-epimerase/4-reductase (WcaG), and α-1,2-fucosyltransferase (Fuct) were co-inoculated, and the multienzyme synthetic pathway was constructed to produce fucosyloligosaccharide using D-mannose as substrate. The product, analyzed by LC/MS, fucosyloligosaccharide was formed under the catalysis of Fuct using GDP-fucose as donor substrate and lactose as acceptor substrate. Fucosyloligosaccharides reached 22 mM by a two-step fermentation compared to 3.7 mM with a one-pot fermentation. CONCLUSIONS: Fucosyloligosaccharide was produced by a two-step fermentation to avoid the inhibitory effect of GDP-fucose on Gmd. Two-step fermentation is a rational synthetic pathway for accumulating fucosyloligosaccharide. [Mh] Termos MeSH primário: Escherichia coli/crescimento & desenvolvimento Fucose/química Manose/metabolismo Complexos Multienzimáticos/genética Oligossacarídeos/biossíntese [Mh] Termos MeSH secundário: Vias Biossintéticas Desidrogenases de Carboidrato/genética Carboidratos Epimerases/genética Escherichia coli/enzimologia Escherichia coli/genética Proteínas de Escherichia coli/genética Fermentação Fucosiltransferases/genética Vetores Genéticos/genética Glucoquinase/genética Guanosina Difosfato Fucose/química Cetona Oxirredutases/genética Lactose/química Complexos Multienzimáticos/metabolismo Nucleotidiltransferases/genética Oligossacarídeos/química Oligossacarídeos/isolamento & purificação Fosfotransferases (Fosfomutases)/genética Transformação Bacteriana [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Escherichia coli Proteins); 0 (Multienzyme Complexes); 0 (Oligosaccharides); 0 (wcaG protein, E coli); 15839-70-0 (Guanosine Diphosphate Fucose); 28RYY2IV3F (Fucose); EC 1.1.- (Carbohydrate Dehydrogenases); EC 1.2.- (Ketone Oxidoreductases); EC 2.4.1.- (Fucosyltransferases); EC 2.7.1.2 (Glucokinase); EC 2.7.7.- (Nucleotidyltransferases); EC 2.7.7.22 (mannose-1-phosphate guanylyltransferase (GDP)); EC 5.1.3.- (Carbohydrate Epimerases); EC 5.4.2.- (Phosphotransferases (Phosphomutases)); EC 5.4.2.8 (phosphomannomutase); J2B2A4N98G (Lactose); PHA4727WTP (Mannose) [Em] Mês de entrada: 1702 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160618 [St] Status: MEDLINE [do] DOI: 10.1007/s10529-016-2151-y

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[PMID]: 27085292 [Au] Autor: Sankarasubramanian J; Vishnu US; Gunasekaran P; Rajendhran J [Ad] Endereço: Department of Genetics, School of Biological Sciences, Madurai Kamaraj University, Madurai 625021, Tamil Nadu, India. [Ti] Título: A genome-wide SNP-based phylogenetic analysis distinguishes different biovars of Brucella suis. [So] Source: Infect Genet Evol;41:213-217, 2016 07. [Is] ISSN: 1567-7257 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: Brucellosis is an important zoonotic disease caused by Brucella spp. Brucella suis is the etiological agent of porcine brucellosis. B. suis is the most genetically diverged species within the genus Brucella. We present the first large-scale B. suis phylogenetic analysis based on an alignment-free k-mer approach of gathering polymorphic sites from whole genome sequences. Genome-wide core-SNP based phylogenetic tree clearly differentiated and discriminated the B. suis biovars and the vaccine strain into different clades. A total of 16,756 SNPs were identified from the genome sequences of 54 B. suis strains. Also, biovar-specific SNPs were identified. The vaccine strain B. suis S2-30 is extensively used in China, which was discriminated from all biovars with the accumulation of the highest number of SNPs. We have also identified the SNPs between B. suis vaccine strain S2-30 and its closest homolog, B. suis biovar 513UK. The highest number of mutations (22) was observed in the phosphomannomutase (pmm) gene essential for the synthesis of O-antigen. Also, mutations were identified in several virulent genes including genes coding for type IV secretion system and the effector proteins, which could be responsible for the attenuated virulence of B. suis S2-30. [Mh] Termos MeSH primário: Proteínas de Bactérias/genética Brucella suis/genética Genoma Bacteriano Mutação Filogenia Polimorfismo de Nucleotídeo Único [Mh] Termos MeSH secundário: Animais Vacinas Bacterianas/genética Sequência de Bases Brucella suis/classificação Brucella suis/patogenicidade Brucelose/epidemiologia Brucelose/microbiologia China/epidemiologia Mapeamento Cromossômico Fosfotransferases (Fosfomutases)/genética Alinhamento de Sequência Suínos Sistemas de Secreção Tipo IV/genética Fatores de Virulência/genética [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Bacterial Proteins); 0 (Bacterial Vaccines); 0 (Type IV Secretion Systems); 0 (Virulence Factors); EC 5.4.2.- (Phosphotransferases (Phosphomutases)); EC 5.4.2.8 (phosphomannomutase) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171117 [Lr] Data última revisão: 171117 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160418 [St] Status: MEDLINE

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[PMID]: 27053713 [Au] Autor: Chan B; Clasquin M; Smolen GA; Histen G; Powe J; Chen Y; Lin Z; Lu C; Liu Y; Cang Y; Yan Z; Xia Y; Thompson R; Singleton C; Dorsch M; Silverman L; Su SM; Freeze HH; Jin S [Ad] Endereço: Agios Pharmaceuticals, Inc., Cambridge, MA 02139-4169, USA. [Ti] Título: A mouse model of a human congenital disorder of glycosylation caused by loss of PMM2. [So] Source: Hum Mol Genet;25(11):2182-2193, 2016 Jun 01. [Is] ISSN: 1460-2083 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The most common congenital disorder of glycosylation (CDG), phosphomannomutase 2 (PMM2)-CDG, is caused by mutations in PMM2 that limit availability of mannose precursors required for protein N-glycosylation. The disorder has no therapy and there are no models to test new treatments. We generated compound heterozygous mice with the R137H and F115L mutations in Pmm2 that correspond to the most prevalent alleles found in patients with PMM2-CDG. Many Pmm2 mice died prenatally, while survivors had significantly stunted growth. These animals and cells derived from them showed protein glycosylation deficiencies similar to those found in patients with PMM2-CDG. Growth-related glycoproteins insulin-like growth factor (IGF) 1, IGF binding protein-3 and acid-labile subunit, along with antithrombin III, were all deficient in Pmm2 mice, but their levels in heterozygous mice were comparable to wild-type (WT) littermates. These imbalances, resulting from defective glycosylation, are likely the cause of the stunted growth seen both in our model and in PMM2-CDG patients. Both Pmm2 mouse and PMM2-CDG patient-derived fibroblasts displayed reductions in PMM activity, guanosine diphosphate mannose, lipid-linked oligosaccharide precursor and total cellular protein glycosylation, along with hypoglycosylation of a new endogenous biomarker, glycoprotein 130 (gp130). Over-expression of WT-PMM2 in patient-derived fibroblasts rescued all these defects, showing that restoration of mutant PMM2 activity is a viable therapeutic strategy. This functional mouse model of PMM2-CDG, in vitro assays and identification of the novel gp130 biomarker all shed light on the human disease, and moreover, provide the essential tools to test potential therapeutics for this untreatable disease. [Mh] Termos MeSH primário: Biomarcadores Defeitos Congênitos da Glicosilação/genética Receptor gp130 de Citocina/genética Fosfotransferases (Fosfomutases)/genética [Mh] Termos MeSH secundário: Animais Defeitos Congênitos da Glicosilação/metabolismo Defeitos Congênitos da Glicosilação/patologia Receptor gp130 de Citocina/biossíntese Modelos Animais de Doenças Fibroblastos/metabolismo Regulação da Expressão Gênica Genótipo Glicosilação Seres Humanos Manose/genética Manose/metabolismo Camundongos Mutação [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Biomarkers); 0 (Il6st protein, mouse); 133483-10-0 (Cytokine Receptor gp130); EC 5.4.2.- (Phosphotransferases (Phosphomutases)); EC 5.4.2.8 (Pmm2 protein, mouse); PHA4727WTP (Mannose) [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: 160408 [St] Status: MEDLINE

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[PMID]: 26951030 [Au] Autor: Sätilä H; Kuusela AL; Pietilä K; Niinikoski H; Keskinen P [Ti] Título: [Congenital disorder of glycosylation type Ia (CDG Ia) - underdiagnosed entity?]. [Ti] Título: Synnynnäinen tyypin Ia glykosylaation häiriö.. [So] Source: Duodecim;132(3):253-9, 2016. [Is] ISSN: 0012-7183 [Cp] País de publicação: Finland [La] Idioma: fin [Ab] Resumo: Congenital disorders of glycosylation (CDG) are a relatively recently identified group of multisystem disorders caused by defective glycosylation of N-glycosylated proteins. They mainly involve the central and peripheral nervous system, but other organ systems are involved as well. Type CDG Ia accounts for over 80% of cases, characterized by decreased activity of the enzyme phosphomannomutase caused by mutations in chromosome 16 PMM2 gene. Treatment of CDG Ia remains symptomatic. [Mh] Termos MeSH primário: Defeitos Congênitos da Glicosilação/diagnóstico Fosfotransferases (Fosfomutases)/deficiência [Mh] Termos MeSH secundário: Cromossomos Humanos Par 16 Defeitos Congênitos da Glicosilação/genética Defeitos Congênitos da Glicosilação/terapia Seres Humanos Mutação Fosfotransferases (Fosfomutases)/genética [Pt] Tipo de publicação: ENGLISH ABSTRACT; JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: EC 5.4.2.- (Phosphotransferases (Phosphomutases)); EC 5.4.2.8 (phosphomannomutase) [Em] Mês de entrada: 1604 [Cu] Atualização por classe: 160308 [Lr] Data última revisão: 160308 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160309 [St] Status: MEDLINE

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MEDLINE

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[PMID]: 26785728 [Au] Autor: Thiesler CT; Cajic S; Hoffmann D; Thiel C; van Diepen L; Hennig R; Sgodda M; Weißmann R; Reichl U; Steinemann D; Diekmann U; Huber NM; Oberbeck A; Cantz T; Kuss AW; Körner C; Schambach A; Rapp E; Buettner FF [Ad] Endereço: From the ‡REBIRTH-Cluster of Excellence, Hannover Medical School, 30625 Hannover, Germany; §Institute for Cellular Chemistry, Hannover Medical School, 30625 Hannover, Germany; [Ti] Título: Glycomic Characterization of Induced Pluripotent Stem Cells Derived from a Patient Suffering from Phosphomannomutase 2 Congenital Disorder of Glycosylation (PMM2-CDG). [So] Source: Mol Cell Proteomics;15(4):1435-52, 2016 Apr. [Is] ISSN: 1535-9484 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: PMM2-CDG, formerly known as congenital disorder of glycosylation-Ia (CDG-Ia), is caused by mutations in the gene encoding phosphomannomutase 2 (PMM2). This disease is the most frequent form of inherited CDG-diseases affecting protein N-glycosylation in human. PMM2-CDG is a multisystemic disease with severe psychomotor and mental retardation. In order to study the pathophysiology of PMM2-CDG in a human cell culture model, we generated induced pluripotent stem cells (iPSCs) from fibroblasts of a PMM2-CDG-patient (PMM2-iPSCs). Expression of pluripotency factors andin vitrodifferentiation into cell types of the three germ layers was unaffected in the analyzed clone PMM2-iPSC-C3 compared with nondiseased human pluripotent stem cells (hPSCs), revealing no broader influence of the PMM2 mutation on pluripotency in cell culture. Analysis of gene expression by deep-sequencing did not show obvious differences in the transcriptome between PMM2-iPSC-C3 and nondiseased hPSCs. By multiplexed capillary gel electrophoresis coupled to laser induced fluorescence detection (xCGE-LIF) we could show that PMM2-iPSC-C3 exhibit the common hPSC N-glycosylation pattern with high-mannose-type N-glycans as the predominant species. However, phosphomannomutase activity of PMM2-iPSC-C3 was 27% compared with control hPSCs and lectin staining revealed an overall reduced protein glycosylation. In addition, quantitative assessment of N-glycosylation by xCGE-LIF showed an up to 40% reduction of high-mannose-type N-glycans in PMM2-iPSC-C3, which was in concordance to the observed reduction of the Glc3Man9GlcNAc2 lipid-linked oligosaccharide compared with control hPSCs. Thus we could model the PMM2-CDG disease phenotype of hypoglycosylation with patient derived iPSCsin vitro Knock-down ofPMM2by shRNA in PMM2-iPSC-C3 led to a residual activity of 5% and to a further reduction of the level of N-glycosylation. Taken together we have developed human stem cell-based cell culture models with stepwise reduced levels of N-glycosylation now enabling to study the role of N-glycosylation during early human development. [Mh] Termos MeSH primário: Defeitos Congênitos da Glicosilação/patologia Glicômica/métodos Células-Tronco Pluripotentes Induzidas/metabolismo Modelos Biológicos Fosfotransferases (Fosfomutases)/deficiência [Mh] Termos MeSH secundário: Células Cultivadas Defeitos Congênitos da Glicosilação/metabolismo Perfilação da Expressão Gênica/métodos Glicosilação Sequenciamento de Nucleotídeos em Larga Escala/métodos Seres Humanos Células-Tronco Pluripotentes Induzidas/patologia Fosfotransferases (Fosfomutases)/metabolismo Polissacarídeos/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Polysaccharides); EC 5.4.2.- (Phosphotransferases (Phosphomutases)) [Em] Mês de entrada: 1612 [Cu] Atualização por classe: 161230 [Lr] Data última revisão: 161230 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160121 [St] Status: MEDLINE [do] DOI: 10.1074/mcp.M115.054122

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