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[PMID]:28456978
[Au] Autor:Lund FW; Wüstner D
[Ad] Endereço:Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230, Odense M, Denmark.
[Ti] Título:Quantitative Co-Localization and Pattern Analysis of Endo-Lysosomal Cargo in Subcellular Image Cytometry and Validation on Synthetic Image Sets.
[So] Source:Methods Mol Biol;1594:93-128, 2017.
[Is] ISSN:1940-6029
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Late endosomes and lysosomes (LE/LYSs) play a central role in trafficking of endocytic cargo, secretion of exosomes, and hydrolysis of ingested proteins and lipids. Failure in such processes can lead to lysosomal storage disorders in which a particular metabolite accumulates within LE/LYSs. Analysis of endocytic trafficking relies heavily on quantitative fluorescence microscopy, but evaluation of the huge image data sets is challenging and demands computer-assisted statistical tools. Here, we describe how to use SpatTrack ( www.sdu.dk/bmb/spattrack ), an imaging toolbox, which we developed for quantification of the distribution and dynamics of endo-lysosomal cargo from fluorescence images of living cells. First, we explain how to analyze experimental images of endocytic processes in Niemann Pick C2 disease fibroblasts using SpatTrack. We demonstrate how to quantify the location of the sterol-binding protein NPC2 in LE/LYSs relative to cholesterol -rich lysosomal storage organelles (LSOs) stained with filipin. Second, we show how to simulate realistic vesicle patterns in the cell geometry using Markov Chain Monte Carlo and suitable inter-vesicle and cell-vesicle interaction potentials. Finally, we use such synthetic vesicle patterns as "ground truth" for validation of two-channel analysis tools in SpatTrack, revealing their high reliability. An improved version of SpatTrack for microscopy-based quantification of cargo transport through the endo-lysosomal system accompanies this protocol.
[Mh] Termos MeSH primário: Endocitose/fisiologia
Endossomos/metabolismo
Lisossomos/metabolismo
[Mh] Termos MeSH secundário: Animais
Colesterol/metabolismo
Seres Humanos
Doenças por Armazenamento dos Lisossomos/metabolismo
Microscopia de Fluorescência
Método de Monte Carlo
Doenças de Niemann-Pick/metabolismo
Transporte Proteico/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
97C5T2UQ7J (Cholesterol)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170501
[St] Status:MEDLINE
[do] DOI:10.1007/978-1-4939-6934-0_6


  2 / 1525 MEDLINE  
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[PMID]:29227082
[Au] Autor:Olkhovych NV
[Ti] Título:Chitotriosidase activity as additional biomarker in the diagnosis of lysosomal storage diseases.
[So] Source:Ukr Biochem J;88(1):69-78, 2016 Jan-Feb.
[Is] ISSN:2409-4943
[Cp] País de publicação:Ukraine
[La] Idioma:eng
[Ab] Resumo:To date, several genetic variants that lead to a deficiency of chitotriosidase activity have been described. The duplication of 24 bp (dup24bp) in exon 10 of the CHIT1 gene, which causes a complete loss of enzymatic activity of the gene product, is the most common among the European population. The aim of the study was to evaluate the possibility of using chitotriosidase activity as an additional biomarker in diagnosis of lysosomal storage diseases (LSDs) in Ukraine, to determine this parameter in blood plasma of the patients with various lysosomal diseases and to assess the effect of the presence of dup24bp in the CHIT1 gene on this parameter. It has been shown that chitotriosidase activity in blood plasma is a convenient additional biochemical marker in the diagnosis of some LSDs, namely Gaucher disease, Niemann-Pick disease A, B, C and GM1-gangliosidosis. Reference ranges of the normal chitotriosidase activity were determined in blood plasma of Ukrainian population and found to be 8.0-53.1 nmol 4-methylumbelliferone/h·ml of plasma. The total allele frequency of the dup24bp in the CHIT1 gene in Ukrainian population was determined, which amounted to 0.26 (323/1244) that is higher than in European population. It was indicated that moleculargenetic screening of dup24bp in the CHIT1 gene is a necessary stage in a protocol for the laboratory diagnosis of Gaucher disease, Niemann-Pick disease A, B, C as well as GM1-gangliosidosis to avoid incorrect diagnosis.
[Mh] Termos MeSH primário: Gangliosidose GM1/genética
Doença de Gaucher/genética
Frequência do Gene
Hexosaminidases/genética
Doenças de Niemann-Pick/genética
[Mh] Termos MeSH secundário: Adulto
Alelos
Biomarcadores/metabolismo
Estudos de Casos e Controles
Éxons
Feminino
Gangliosidose GM1/classificação
Gangliosidose GM1/diagnóstico
Gangliosidose GM1/patologia
Doença de Gaucher/diagnóstico
Doença de Gaucher/patologia
Duplicação Gênica
Expressão Gênica
Testes Genéticos
Hexosaminidases/sangue
Hexosaminidases/deficiência
Seres Humanos
Himecromona/sangue
Masculino
Doenças de Niemann-Pick/classificação
Doenças de Niemann-Pick/diagnóstico
Doenças de Niemann-Pick/patologia
Ucrânia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 3T5NG4Q468 (Hymecromone); EC 3.2.1.- (Hexosaminidases); EC 3.2.1.- (chitotriosidase)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171212
[St] Status:MEDLINE
[do] DOI:10.15407/ubj88.01.069


  3 / 1525 MEDLINE  
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[PMID]:28626941
[Au] Autor:Sezgin E; Azbazdar Y; Ng XW; Teh C; Simons K; Weidinger G; Wohland T; Eggeling C; Ozhan G
[Ad] Endereço:MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, UK.
[Ti] Título:Binding of canonical Wnt ligands to their receptor complexes occurs in ordered plasma membrane environments.
[So] Source:FEBS J;284(15):2513-2526, 2017 Aug.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:While the cytosolic events of Wnt/ß-catenin signaling (canonical Wnt signaling) pathway have been widely studied, only little is known about the molecular mechanisms involved in Wnt binding to its receptors at the plasma membrane. Here, we reveal the influence of the immediate plasma membrane environment on the canonical Wnt-receptor interaction. While the receptors are distributed both in ordered and disordered environments, Wnt binding to its receptors selectively occurs in more ordered membrane environments which appear to cointernalize with the Wnt-receptor complex. Moreover, Wnt/ß-catenin signaling is significantly reduced when the membrane order is disturbed by specific inhibitors of certain lipids that prefer to localize at the ordered environments. Similarly, a reduction in Wnt signaling activity is observed in Niemann-Pick Type C disease cells where trafficking of ordered membrane lipid components to the plasma membrane is genetically impaired. We thus conclude that ordered plasma membrane environments are essential for binding of canonical Wnts to their receptor complexes and downstream signaling activity.
[Mh] Termos MeSH primário: Membrana Celular/metabolismo
Proteínas do Citoesqueleto/metabolismo
Microdomínios da Membrana/metabolismo
Receptores Wnt/agonistas
Proteínas Wnt/metabolismo
Via de Sinalização Wnt
Proteína Wnt3/metabolismo
Proteína Wnt3A/metabolismo
Proteínas de Peixe-Zebra/metabolismo
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Células CHO
Linhagem Celular Tumoral
Células Cultivadas
Cricetulus
Proteínas do Citoesqueleto/genética
Embrião não Mamífero/metabolismo
Genes Reporter
Células HEK293
Seres Humanos
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/agonistas
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo
Proteínas Luminescentes/genética
Proteínas Luminescentes/metabolismo
Doenças de Niemann-Pick/metabolismo
Doenças de Niemann-Pick/patologia
Receptores Wnt/metabolismo
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Wnt/genética
Proteína Wnt3/genética
Proteína Wnt3A/genética
Peixe-Zebra/genética
Peixe-Zebra/metabolismo
Proteínas de Peixe-Zebra/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytoskeletal Proteins); 0 (Low Density Lipoprotein Receptor-Related Protein-6); 0 (Luminescent Proteins); 0 (Receptors, Wnt); 0 (Recombinant Fusion Proteins); 0 (Wnt Proteins); 0 (Wnt3 Protein); 0 (Wnt3A Protein); 0 (Wnt3a protein, zebrafish); 0 (Zebrafish Proteins); 0 (wnt8a protein, zebrafish)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170620
[St] Status:MEDLINE
[do] DOI:10.1111/febs.14139


  4 / 1525 MEDLINE  
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[PMID]:28550066
[Au] Autor:Hildreth A; Wigby K; Chowdhury S; Nahas S; Barea J; Ordonez P; Batalov S; Dimmock D; Kingsmore S; RCIGM Investigators
[Ad] Endereço:Rady Children's Institute of Genomic Medicine, San Diego, California 92123, USA.
[Ti] Título:Rapid whole-genome sequencing identifies a novel homozygous variant associated with Niemann-Pick type C1 disease in a 7-week-old male with cholestasis.
[So] Source:Cold Spring Harb Mol Case Stud;3(5), 2017 Sep.
[Is] ISSN:2373-2873
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Niemann-Pick type C disease (NPC; OMIM #257220) is an inborn error of intracellular cholesterol trafficking. It is an autosomal recessive disorder caused predominantly by mutations in Although characterized as a progressive neurological disorder, it can also cause cholestasis and liver dysfunction because of intrahepatocyte lipid accumulation. We report a 7-wk-old infant who was admitted with neonatal cholestasis, and who was diagnosed with a novel homozygous stop-gain variant in by rapid whole-genome sequencing (WGS). WGS results were obtained 16 d before return of the standard clinical genetic test results and prompted initiation of targeted therapy.
[Mh] Termos MeSH primário: Proteínas de Transporte/genética
Glicoproteínas de Membrana/genética
Doença de Niemann-Pick Tipo C/diagnóstico
Doença de Niemann-Pick Tipo C/genética
[Mh] Termos MeSH secundário: Proteínas de Transporte/metabolismo
Colestase/complicações
Colestase/genética
Colesterol/genética
Colesterol/metabolismo
Genoma/genética
Homozigoto
Seres Humanos
Lactente
Hepatopatias/complicações
Masculino
Glicoproteínas de Membrana/metabolismo
Mutação
Doença de Niemann-Pick Tipo C/complicações
Doença de Niemann-Pick Tipo C/metabolismo
Doenças de Niemann-Pick/complicações
Doenças de Niemann-Pick/genética
Análise de Sequência de DNA/métodos
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Membrane Glycoproteins); 0 (NPC1 protein, human); 97C5T2UQ7J (Cholesterol)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170528
[St] Status:MEDLINE


  5 / 1525 MEDLINE  
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[PMID]:28164782
[Au] Autor:Schuchman EH; Desnick RJ
[Ad] Endereço:Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, United States. Electronic address: edward.schuchman@mssm.edu.
[Ti] Título:Types A and B Niemann-Pick disease.
[So] Source:Mol Genet Metab;120(1-2):27-33, 2017 Jan - Feb.
[Is] ISSN:1096-7206
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The eponym Niemann-Pick disease (NPD) refers to a group of patients who present with varying degrees of lipid storage and foam cell infiltration in tissues, as well as overlapping clinical features including hepatosplenomegaly, pulmonary insufficiency and/or central nervous system (CNS) involvement. Due to the pioneering work of Roscoe Brady and co-workers, we now know that there are two distinct metabolic abnormalities that account for NPD. The first is due to the deficient activity of the enzyme acid sphingomyelinase (ASM; "types A & B" NPD), and the second is due to defective function in cholesterol transport ("type C" NPD). Herein only types A and B NPD will be discussed. Type A NPD patients exhibit hepatosplenomegaly in infancy and profound CNS involvement. They rarely survive beyond 2-3years of age. Type B patients also have hepatosplenomegaly and pathologic alterations of their lungs, but there are usually no CNS signs. The age of onset and rate of disease progression varies greatly among type B patients, and they frequently live into adulthood. Intermediate patients also have been reported with mild to moderate neurological findings. All patients with types A and B NPD have mutations in the gene encoding ASM (SMPD1), and thus the disease is more accurately referred to as ASM deficiency (ASMD). Herein we will review the clinical, pathological, biochemical, and genetic findings in types A and B NPD, and emphasize the seminal contributions of Dr. Brady to this disease. We will also discuss the current status of therapy for this disorder.
[Mh] Termos MeSH primário: Colesterol/metabolismo
Doenças de Niemann-Pick/classificação
Esfingomielina Fosfodiesterase/deficiência
[Mh] Termos MeSH secundário: Idade de Início
Animais
Progressão da Doença
Feminino
História do Século XX
História do Século XXI
Seres Humanos
Masculino
Mutação
Doenças de Niemann-Pick/genética
Esfingomielina Fosfodiesterase/genética
[Pt] Tipo de publicação:BIOGRAPHY; HISTORICAL ARTICLE; JOURNAL ARTICLE; REVIEW
[Ps] Nome de pessoa como assunto:Brady RO
[Nm] Nome de substância:
97C5T2UQ7J (Cholesterol); EC 3.1.4.12 (Sphingomyelin Phosphodiesterase); EC 3.1.4.12 (sphingomyelin phosphodiesterase 1, human)
[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:170207
[St] Status:MEDLINE


  6 / 1525 MEDLINE  
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[PMID]:28126847
[Au] Autor:Abdul-Hammed M; Breiden B; Schwarzmann G; Sandhoff K
[Ad] Endereço:Life and Medical Sciences (LIMES) Institut, Membrane Biology and Lipid Biochemistry Unit, Kekulé-Institut für Organische Chemie und Biochemie, Universität Bonn, Bonn, Germany.
[Ti] Título:Lipids regulate the hydrolysis of membrane bound glucosylceramide by lysosomal ß-glucocerebrosidase.
[So] Source:J Lipid Res;58(3):563-577, 2017 Mar.
[Is] ISSN:1539-7262
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glucosylceramide (GlcCer) is the primary storage lipid in the lysosomes of Gaucher patients and a secondary one in Niemann-Pick disease types A, B, and C. The regulatory roles of lipids on the hydrolysis of membrane bound GlcCer by lysosomal ß-glucocerebrosidase (GBA1) was probed using a detergent-free liposomal assay. The degradation rarely occurs at uncharged liposomal surfaces in the absence of saposin (Sap) C. However, anionic lipids stimulate GlcCer hydrolysis at low pH by up to 1,000-fold depending on the nature and position of the negative charges in their head groups while cationic lipids inhibit the degradation, thus showing the importance of electrostatic interactions between the polycationic GBA1 and the negatively charged vesicle surfaces at low pH. Ceramide, fatty acids, monoacylglycerol, and diacylglycerol also stimulate GlcCer hydrolysis while SM, sphingosine, and sphinganine play strong inhibitory roles, thereby explaining the secondary storage of GlcCer in Niemann-Pick diseases. Surprisingly, cholesterol stimulates GlcCer degradation in the presence of bis(monoacylglycero)phosphate (BMP). Sap C strongly stimulates GlcCer hydrolysis even in the absence of BMP and the regulatory roles of the intraendolysosomal lipids on its activity is discussed. Our data suggest that these strong modifiers of GlcCer hydrolysis affect the genotype-phenotype correlation in several cases of Gaucher patients independent of the types.
[Mh] Termos MeSH primário: Doença de Gaucher/metabolismo
Glucosilceramidase/genética
Glucosilceramidas/metabolismo
Doenças de Niemann-Pick/metabolismo
[Mh] Termos MeSH secundário: Colesterol/metabolismo
Doença de Gaucher/genética
Doença de Gaucher/patologia
Estudos de Associação Genética
Glucosilceramidase/metabolismo
Seres Humanos
Hidrólise
Metabolismo dos Lipídeos/genética
Lisofosfolipídeos/metabolismo
Lisossomos/enzimologia
Monoglicerídeos/metabolismo
Doenças de Niemann-Pick/genética
Doenças de Niemann-Pick/patologia
Saposinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glucosylceramides); 0 (Lysophospholipids); 0 (Monoglycerides); 0 (Saposins); 0 (bis(monoacylglyceryl)phosphate); 97C5T2UQ7J (Cholesterol); EC 3.2.1.45 (Glucosylceramidase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170828
[Lr] Data última revisão:
170828
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170128
[St] Status:MEDLINE
[do] DOI:10.1194/jlr.M073510


  7 / 1525 MEDLINE  
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[PMID]:27876313
[Au] Autor:Valayannopoulos V; Mengel E; Brassier A; Grabowski G
[Ad] Endereço:Hôpital Necker, Enfants Malades, Paris, France; Sanofi Genzyme Corporation, Cambridge, MA, USA. Electronic address: vassilival.boston@gmail.com.
[Ti] Título:Lysosomal acid lipase deficiency: Expanding differential diagnosis.
[So] Source:Mol Genet Metab;120(1-2):62-66, 2017 Jan - Feb.
[Is] ISSN:1096-7206
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The differential diagnoses for metabolic liver diseases may be challenging in clinical settings, which represents a critical issue for disorders such as lysosomal acid lipase deficiency (LAL-D). LAL-D is caused by deficient activity of the LAL enzyme, resulting in the accumulation of cholesteryl esters and triglycerides throughout the body, predominately in the liver, spleen, gastrointestinal tract, and blood vessel walls. LAL-D is a progressive, multi-organ disease with early mortality and significant morbidity characterized by a combination of hepatic dysfunction and dyslipidemia. Evidence suggests LAL-D may be substantially underdiagnosed or misdiagnosed, which is critical given that disease progression can be unpredictable, with liver failure and/or accelerated atherosclerosis potentially contributing to early mortality. However, given the development of a simple diagnostic test and recently approved treatment, LAL-D should be incorporated into the differential diagnosis in relevant clinical settings. LAL-D can be diagnosed using an LAL enzyme-based biochemical test, thereby allowing for active monitoring of patients to detect potential disease complications and consider treatment options including diet, lipid-lowering medication, and treatment with sebelipase alfa, a recombinant enzyme replacement therapy shown to provide clinical benefit and improve disease-relevant markers in clinical trials. To illustrate the complexity of diagnosing LAL-D, this manuscript will describe the path to diagnosing LAL-D in a series of patient cases in which LAL-D was diagnosed as well as in patients where other diseases, such as Gaucher disease and Niemann-Pick disease, were initially suspected.
[Mh] Termos MeSH primário: Esterol Esterase/metabolismo
Esterol Esterase/uso terapêutico
Doença de Wolman/diagnóstico
Doença de Wolman/tratamento farmacológico
[Mh] Termos MeSH secundário: Adolescente
Criança
Ésteres do Colesterol/metabolismo
Diagnóstico Diferencial
Progressão da Doença
Diagnóstico Precoce
Feminino
Doença de Gaucher/metabolismo
Seres Humanos
Lactente
Masculino
Doenças de Niemann-Pick/metabolismo
Triglicerídeos/metabolismo
Doença de Wolman/metabolismo
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cholesterol Esters); 0 (Triglycerides); EC 3.1.1.13 (LIPA protein, human); EC 3.1.1.13 (Sterol Esterase); K4YTU42T8G (Sebelipase alfa)
[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:161124
[St] Status:MEDLINE


  8 / 1525 MEDLINE  
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[PMID]:27798705
[Au] Autor:Canonico B; Cesarini E; Salucci S; Luchetti F; Falcieri E; Di Sario G; Palma F; Papa S
[Ad] Endereço:Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.
[Ti] Título:Defective Autophagy, Mitochondrial Clearance and Lipophagy in Niemann-Pick Type B Lymphocytes.
[So] Source:PLoS One;11(10):e0165780, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Niemann-Pick disease type A (NP-A) and type B (NP-B) are lysosomal storage diseases (LSDs) caused by sphingomyelin accumulation in lysosomes relying on reduced or absent acid sphingomyelinase. A considerable body of evidence suggests that lysosomal storage in many LSD impairs autophagy, resulting in the accumulation of poly-ubiquitinated proteins and dysfunctional mitochondria, ultimately leading to cell death. Here we test this hypothesis in a cellular model of Niemann-Pick disease type B, in which autophagy has never been studied. The basal autophagic pathway was first examined in order to evaluate its functionality using several autophagy-modulating substances such as rapamycin and nocodazole. We found that human NP-B B lymphocytes display considerable alteration in their autophagic vacuole accumulation and mitochondrial fragmentation, as well as mitophagy induction (for damaged mitochondria clearance). Furthermore, lipid traceability of intra and extra-cellular environments shows lipid accumulation in NP-B B lymphocytes and also reveals their peculiar trafficking/management, culminating in lipid microparticle extrusion (by lysosomal exocytosis mechanisms) or lipophagy. All of these features point to the presence of a deep autophagy/mitophagy alteration revealing autophagic stress and defective mitochondrial clearance. Hence, rapamycin might be used to regulate autophagy/mitophagy (at least in part) and to contribute to the clearance of lysosomal aberrant lipid storage.
[Mh] Termos MeSH primário: Autofagia
Linfócitos B/metabolismo
Metabolismo dos Lipídeos
Mitocôndrias/metabolismo
Doenças de Niemann-Pick/metabolismo
[Mh] Termos MeSH secundário: Linfócitos B/ultraestrutura
Biomarcadores
Micropartículas Derivadas de Células/metabolismo
Endocitose
Exocitose
Espaço Extracelular/metabolismo
Citometria de Fluxo
Seres Humanos
Espaço Intracelular/metabolismo
Lisossomos/metabolismo
Mitocôndrias/ultraestrutura
Degradação Mitocondrial
Fagossomos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170615
[Lr] Data última revisão:
170615
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161101
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0165780


  9 / 1525 MEDLINE  
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[PMID]:27659707
[Au] Autor:Acuña M; Castro-Fernández V; Latorre M; Castro J; Schuchman EH; Guixé V; González M; Zanlungo S
[Ad] Endereço:Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Center of Genome Regulation (Fondap 15090007), Universidad de Chile, Santiago, Chile. Electronic address: mariana.acuna1@gmail.com.
[Ti] Título:Structural and functional analysis of the ASM p.Ala359Asp mutant that causes acid sphingomyelinase deficiency.
[So] Source:Biochem Biophys Res Commun;479(3):496-501, 2016 Oct 21.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Niemann-Pick disease (NPD) type A and B are recessive hereditary disorders caused by deficiency in acid sphingomyelinase (ASM). The p.Ala359Asp mutation has been described in several patients but its functional and structural effects in the protein are unknown. In order to characterize this mutation, we modeled the three-dimensional ASM structure using the recent available crystal of the mammalian ASM as a template. We found that the p.Ala359Asp mutation is localized in the hydrophobic core and far from the sphingomyelin binding site. However, energy function calculations using statistical potentials indicate that the mutation causes a decrease in ASM stability. Therefore, we investigated the functional effect of the p.Ala359Asp mutation in ASM expression, secretion, localization and activity in human fibroblasts. We found a 3.8% residual ASM activity compared to the wild-type enzyme, without changes in the other parameters evaluated. These results support the hypothesis that the p.Ala359Asp mutation causes structural alterations in the hydrophobic environment where ASM is located, decreasing its enzymatic activity. A similar effect was observed in other previously described NPDB mutations located outside the active site of the enzyme. This work shows the first full size ASM mutant model describe at date, providing a complete analysis of the structural and functional effects of the p.Ala359Asp mutation over the stability and activity of the enzyme.
[Mh] Termos MeSH primário: Doenças de Niemann-Pick/genética
Esfingomielina Fosfodiesterase/metabolismo
[Mh] Termos MeSH secundário: Alanina/química
Ácido Aspártico/química
Domínio Catalítico
Fibroblastos/metabolismo
Seres Humanos
Substâncias Macromoleculares
Microscopia de Fluorescência
Conformação Molecular
Mutação
Doenças de Niemann-Pick/metabolismo
Domínios Proteicos
Esfingomielina Fosfodiesterase/deficiência
Esfingomielina Fosfodiesterase/genética
Eletricidade Estática
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Macromolecular Substances); 30KYC7MIAI (Aspartic Acid); EC 3.1.4.12 (Sphingomyelin Phosphodiesterase); EC 3.1.4.12 (sphingomyelin phosphodiesterase 1, human); OF5P57N2ZX (Alanine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170827
[Lr] Data última revisão:
170827
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160924
[St] Status:MEDLINE


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Fotocópia
[PMID]:27453965
[Au] Autor:Sandoval-Sus JD; Zhang L
[Ti] Título:Familial hypertriglyceridemia manifests with pancytopenia and bone marrow pseudo­Niemann-Pick cells.
[So] Source:Blood;127(6):787, 2016 Feb 11.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Células da Medula Óssea/patologia
Hiperlipoproteinemia Tipo IV/diagnóstico
Pancitopenia/diagnóstico
[Mh] Termos MeSH secundário: Diagnóstico Diferencial
Seres Humanos
Masculino
Meia-Idade
Doenças de Niemann-Pick/diagnóstico
Doenças de Niemann-Pick/patologia
Pancitopenia/etiologia
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Em] Mês de entrada:1607
[Cu] Atualização por classe:160722
[Lr] Data última revisão:
160722
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:160726
[St] Status:MEDLINE



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