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https://www.readbyqxmd.com/read/27905362/-characteristics-of-parkinson-s-disease-course-in-the-heterozygous-carriage-of-mutations-in-the-glucocerebrosidase-a-gene
#1
O A Gan'kina, E E Vasenina, O S Levin, E Yu Fedotova, S N Illarioshkin
Parkinson's disease (PD) is a common neurodegenerative disease. Literature sources indicate the association of PD and mutations in the glucocerebrosidase A (GBA) gene. According to our study, the frequency of the two most common mutations in the GBA gene, N370S and L444P, is 1.85%. Mutation carriers have slower progression of motor symptoms, but are more likely to develop drug-induced motor fluctuations and dyskinesia. In carriers of GBA mutations, the severity of cognitive impairment corresponds to age-matched patients without mutations...
2016: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
https://www.readbyqxmd.com/read/27872820/nine-year-experience-in-gaucher-disease-diagnosis-at-the-spanish-reference-center-fundaci%C3%A3-n-jim%C3%A3-nez-d%C3%A3-az
#2
N V Ortiz-Cabrera, J Gallego-Merlo, C Vélez-Monsalve, R de Nicolas, S Fontao Mas, C Ayuso, M J Trujillo-Tiebas
BACKGROUND: Fundación Jiménez Díaz (FJD) is a reference center for genetic diagnosis of Gaucher disease (GD) in Spain. Genetic analyses of acid β-glucosidase (GBA) gene using different techniques were performed to search for new mutations, in addition to those previously and most frequently found in the Spanish population. Additionally, the study of the chitotriosidase (CHIT1) gene was used to assess the inflammatory status of patients in the follow-up of enzyme replacement therapy (ERT)...
December 2016: Molecular Genetics and Metabolism Reports
https://www.readbyqxmd.com/read/27864021/trio-approach-reveals-higher-risk-of-pd-in-carriers-of-severe-vs-mild-gba-mutations
#3
David Arkadir, Tama Dinur, Stephen Mullin, Atul Mehta, Hagit N Baris, Roy N Alcalay, Ari Zimran
Heterozygote GBA (glucosylceramidase beta) mutations increase the risk of Parkinson's disease (PD). Data based on the measured frequencies of GBA mutated alleles in the healthy population suggest that severe GBA mutations are associated with even higher risk for PD. These data, however, are prone to methodological biases resulting from the rarity of severe mutations and from ethnic-dependent differences in allele frequencies. To overcome these biases, we traced 13 Gaucher disease (GD) patients who were compound heterozygotes for one mild (N370S) and one severe GBA mutation and who reported a parent with PD...
November 12, 2016: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/27816428/ferritinemia-and-serum-inflammatory-cytokines-in-swedish-adults-with-gaucher-disease-type-1
#4
Fryderyk Lorenz, Ewa Pawłowicz, Monika Klimkowska, Soheir Beshara, Agnes Bulanda Brustad, Aleksander B Skotnicki, Anders Wahlin, Maciej Machaczka
BACKGROUND: The storage of glucosylceramide in macrophages produces an inflammatory response in Gaucher disease type 1 (GD1) resulting in iron metabolism dysregulation and cytokine release. PATIENTS AND METHODS: The study included 16 adults with GD1 aged 20-86years. All but one patient carried at least one allele with the c.1226A>G (N370S) mutation in the GBA1 gene. Ferritinemia, iron metabolism profiles including hepcidin, and inflammatory cytokine concentrations were assessed in GD1 patients in Sweden...
October 20, 2016: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/27777137/autosomal-dominant-parkinson-s-disease-incidence-of-mutations-in-lrrk2-snca-vps35-and-gba-genes-in-brazil
#5
Gabriella de M Abreu, Débora Cristina T Valença, Mário Campos, Camilla P da Silva, João S Pereira, Marco A Araujo Leite, Ana Lucia Rosso, Denise H Nicaretta, Luiz Felipe R Vasconcellos, Delson José da Silva, Marcus V Della Coletta, Jussara M Dos Santos, Andressa P Gonçalves, Cíntia B Santos-Rebouças, Márcia M G Pimentel
INTRODUCTION: Amongst Parkinson's disease (PD) genetic factors, mutations in LRRK2, SNCA, VPS35 and GBA genes are recognized causes of PD. Nonetheless, few genetic screenings have been conducted in families with a history of PD consistent with autosomal dominant inheritance (ADPD), and their relevance to the etiology of PD has been poorly explored in Latin American populations, such as the Brazilian one, with a high degree of admixture. METHODS: In order to assess the contribution of specific mutations in LRRK2, SNCA, VPS35 and GBA genes to ADPD in Brazil, we conducted the first molecular evaluation in a cohort of 141 index cases from families with ADPD...
December 2, 2016: Neuroscience Letters
https://www.readbyqxmd.com/read/27723713/-characteristics-of-parkinson-s-disease-course-in-the-heterozygous-carriage-of-mutations-in-the-glucocerebrosidase-a-gene
#6
O A Gan'kina, E E Vasenina, O S Levin, E Yu Fedotova, S N Illarioshkin
Parkinson's disease (PD) is a common neurodegenerative disease. Literature sources indicate the association of PD and mutations in the glucocerebrosidase A (GBA) gene. According to our study, the frequency of the two most common mutations in the GBA gene, N370S and L444P, is 1.85%. Mutation carriers have slower progression of motor symptoms, but are more likely to develop drug-induced motor fluctuations and dyskinesia. In carriers of GBA mutations, the severity of cognitive impairment corresponds to age-matched patients without mutations...
2016: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
https://www.readbyqxmd.com/read/27717005/specifically-neuropathic-gaucher-s-mutations-accelerate-cognitive-decline-in-parkinson-s
#7
Ganqiang Liu, Brendon Boot, Joseph J Locascio, Iris E Jansen, Sophie Winder-Rhodes, Shirley Eberly, Alexis Elbaz, Alexis Brice, Bernard Ravina, Jacobus J van Hilten, Florence Cormier-Dequaire, Jean-Christophe Corvol, Roger A Barker, Peter Heutink, Johan Marinus, Caroline H Williams-Gray, Clemens R Scherzer
OBJECTIVE: We hypothesized that specific mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates. METHODS: A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models...
November 2016: Annals of Neurology
https://www.readbyqxmd.com/read/27632223/survival-and-dementia-in-gba-associated-parkinson-s-disease-the-mutation-matters
#8
Roberto Cilia, Sara Tunesi, Giorgio Marotta, Emanuele Cereda, Chiara Siri, Silvana Tesei, Anna L Zecchinelli, Margherita Canesi, Claudio B Mariani, Nicoletta Meucci, Giorgio Sacilotto, Michela Zini, Michela Barichella, Corrado Magnani, Stefano Duga, Rosanna Asselta, Giulia Soldà, Agostino Seresini, Manuela Seia, Gianni Pezzoli, Stefano Goldwurm
OBJECTIVE: The objective of this work was to investigate survival, dementia, and genotype-phenotype correlations in patients with Parkinson's disease (PD) with and without mutations on the glucocerebrosidase gene (GBA). METHODS: We included 2,764 unrelated consecutive PD patients: 123 GBA carriers (67 mild-p.N370S and 56 severe mainly p.L444P) and 2,641 noncarriers. Brain perfusion and dopamine transporter imaging was analyzed, including dementia with Lewy Bodies (DLB) as an additional control group...
September 15, 2016: Annals of Neurology
https://www.readbyqxmd.com/read/27598312/design-and-synthesis-of-potent-quinazolines-as-selective-%C3%AE-glucocerebrosidase-modulators
#9
Jianbin Zheng, Long Chen, Michael Schwake, Richard B Silverman, Dimitri Krainc
Gaucher's disease is a common genetic disease caused by mutations in the β-glucocerebrosidase (GBA1) gene that have been also linked to increased risk of Parkinson's disease and Lewy body dementia. Stabilization of misfolded mutant β-glucocerebrosidase (GCase) represents an important therapeutic strategy in synucleinopathies. Here we report a novel class of GCase quinazoline inhibitors, obtained in a high throughput screening, with moderate potency against wild-type GCase. Rational design and a SAR study of this class of compounds led to a new series of quinazoline derivatives with single-digit nanomolar potency...
September 22, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27539639/parkinson-disease-linked-gba-mutation-effects-reversed-by-molecular-chaperones-in-human-cell-and-fly-models
#10
Alvaro Sanchez-Martinez, Michelle Beavan, Matthew E Gegg, Kai-Yin Chau, Alexander J Whitworth, Anthony H V Schapira
GBA gene mutations are the greatest cause of Parkinson disease (PD). GBA encodes the lysosomal enzyme glucocerebrosidase (GCase) but the mechanisms by which loss of GCase contributes to PD remain unclear. Inhibition of autophagy and the generation of endoplasmic reticulum (ER) stress are both implicated. Mutant GCase can unfold in the ER and be degraded via the unfolded protein response, activating ER stress and reducing lysosomal GCase. Small molecule chaperones that cross the blood brain barrier help mutant GCase refold and traffic correctly to lysosomes are putative treatments for PD...
August 19, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27393345/genome-wide-assessment-of-parkinson-s-disease-in-a-southern-spanish-population
#11
Sara Bandrés-Ciga, Timothy Ryan Price, Francisco Javier Barrero, Francisco Escamilla-Sevilla, Javier Pelegrina, Sampath Arepalli, Dena Hernández, Blanca Gutiérrez, Jorge Cervilla, Margarita Rivera, Alberto Rivera, Jing-Hui Ding, Francisco Vives, Michael Nalls, Andrew Singleton, Raquel Durán
Here, we set out to study the genetic architecture of Parkinson's disease (PD) through a Genome-Wide Association Study in a Southern Spanish population. About 240 PD cases and 192 controls were genotyped on the NeuroX array. We estimated genetic variation associated with PD risk and age at onset (AAO). Risk profile analyses for PD and AAO were performed using a weighted genetic risk score. Total heritability was estimated by genome-wide complex trait analysis. Rare variants were screened with single-variant and burden tests...
September 2016: Neurobiology of Aging
https://www.readbyqxmd.com/read/27255555/strong-association-between-glucocerebrosidase-mutations-and-parkinson-s-disease-in-sweden
#12
Caroline Ran, Lovisa Brodin, Lars Forsgren, Marie Westerlund, Mehrafarin Ramezani, Sandra Gellhaar, Fengqing Xiang, Camilla Fardell, Hans Nissbrandt, Peter Söderkvist, Andreas Puschmann, Emil Ygland, Lars Olson, Thomas Willows, Anders Johansson, Olof Sydow, Karin Wirdefeldt, Dagmar Galter, Per Svenningsson, Andrea Carmine Belin
Several genetic studies have demonstrated an association between mutations in glucocerebrosidase (GBA), originally implicated in Gaucher's disease, and an increased risk of Parkinson's disease (PD). We have investigated the possible involvement of genetic GBA variations in PD in the Swedish population. Three GBA variants, E326K, N370S, and L444P were screened in the largest Swedish Parkinson cohort reported to date; 1625 cases and 2025 control individuals. We found a significant association with high effect size of the rare variant L444P with PD (odds ratio 8...
September 2016: Neurobiology of Aging
https://www.readbyqxmd.com/read/27222815/identification-of-novel-splice-site-mutation-ivs9%C3%A2-%C3%A2-1-g%C3%A2-%C3%A2-a-and-novel-complex-allele-g355r-r359x-in-type-1-gaucher-patients-heterozygous-for-mutation-n370s
#13
Kourtnee Hoitsema, Dominick Amato, Aneal Khan, Sandra Sirrs, Francis Y M Choy
Gaucher disease is an autosomal recessive lysosomal storage disorder resulting from deficient glucocerebrosidase activity. More than 350 mutations that cause Gaucher disease have been described to date. Novel mutations can potentially provide insight into the glucocerebrosidase structure-function relationship and biochemical basis of the disease. Here, we report the identification of two novel mutations in two unrelated patients with type I (non-neuronopathic) Gaucher disease: 1) a splice site mutation IVS9 + 1G > A; and (2) a complex allele (cis) G355R/R359X...
September 2016: Meta Gene
https://www.readbyqxmd.com/read/27162249/the-contribution-of-mutant-gba-to-the-development-of-parkinson-disease-in-drosophila
#14
Gali Maor, Or Cabasso, Olga Krivoruk, Joe Rodriguez, Hermann Steller, Daniel Segal, Mia Horowitz
Gaucher disease (GD) results from mutations in the acid β-glucocerebrosidase (GCase) encoding gene, GBA, which leads to accumulation of glucosylceramides. GD patients and carriers of GD mutations have a significantly higher propensity to develop Parkinson disease (PD) in comparison to the non-GD population. In this study, we used the fruit fly Drosophila melanogaster to show that development of PD in carriers of GD mutations results from the presence of mutant GBA alleles. Drosophila has two GBA orthologs (CG31148 and CG31414), each of which has a minos insertion, which creates C-terminal deletion in the encoded GCase...
May 9, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/27001828/characterization-of-the-complex-formed-by-%C3%AE-glucocerebrosidase-and-the-lysosomal-integral-membrane-protein-type-2
#15
Friederike Zunke, Lisa Andresen, Sophia Wesseler, Johann Groth, Philipp Arnold, Michelle Rothaug, Joseph R Mazzulli, Dimitri Krainc, Judith Blanz, Paul Saftig, Michael Schwake
The lysosomal integral membrane protein type-2 (LIMP-2) plays a pivotal role in the delivery of β-glucocerebrosidase (GC) to lysosomes. Mutations in GC result in Gaucher's disease (GD) and are the major genetic risk factor for the development of Parkinson's disease (PD). Variants in the LIMP-2 gene cause action myoclonus-renal failure syndrome and also have been linked to PD. Given the importance of GC and LIMP-2 in disease pathogenesis, we studied their interaction sites in more detail. Our previous data demonstrated that the crystal structure of LIMP-2 displays a hydrophobic three-helix bundle composed of helices 4, 5, and 7, of which helix 5 and 7 are important for ligand binding...
April 5, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/26905200/er-stress-and-autophagic-perturbations-lead-to-elevated-extracellular-%C3%AE-synuclein-in-gba-n370s-parkinson-s-ipsc-derived-dopamine-neurons
#16
Hugo J R Fernandes, Elizabeth M Hartfield, Helen C Christian, Evangelia Emmanoulidou, Ying Zheng, Heather Booth, Helle Bogetofte, Charmaine Lang, Brent J Ryan, S Pablo Sardi, Jennifer Badger, Jane Vowles, Samuel Evetts, George K Tofaris, Kostas Vekrellis, Kevin Talbot, Michele T Hu, William James, Sally A Cowley, Richard Wade-Martins
Heterozygous mutations in the glucocerebrosidase gene (GBA) represent the strongest common genetic risk factor for Parkinson's disease (PD), the second most common neurodegenerative disorder. However, the molecular mechanisms underlying this association are still poorly understood. Here, we have analyzed ten independent induced pluripotent stem cell (iPSC) lines from three controls and three unrelated PD patients heterozygous for the GBA-N370S mutation, and identified relevant disease mechanisms. After differentiation into dopaminergic neurons, we observed misprocessing of mutant glucocerebrosidase protein in the ER, associated with activation of ER stress and abnormal cellular lipid profiles...
March 8, 2016: Stem Cell Reports
https://www.readbyqxmd.com/read/26868973/mutations-of-glucocerebrosidase-gene-and-susceptibility-to-parkinson-s-disease-an-updated-meta-analysis-in-a-european-population
#17
F Zhao, L Bi, W Wang, X Wu, Y Li, F Gong, S Lu, F Feng, Z Qian, C Hu, Y Wu, Y Sun
This meta-analysis aims to investigate the association between mutations of glucocerebrosidase (GBA) gene and susceptibility to Parkinson's disease (PD) in a European population. Several electronic databases were extensively searched. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the association. In total, fourteen published papers screening L444P, N370S and other GBA variants were identified. The GBA mutations were significantly associated with PD in the European population...
April 21, 2016: Neuroscience
https://www.readbyqxmd.com/read/26792850/residual-enzymatic-activity-as-a-prognostic-factor-in-patients-with-gaucher-disease-type-1-correlation-with-zimran-and-gauss-i-index-and-the-severity-of-bone-disease
#18
M A Torralba, S Olivera, J C Bureo, J Dalmau, R Nuñez, P León, J Villarrubia
BACKGROUND: Gaucher disease (GD) is an autosomal recessive disorder produced by mutations in the glucocerebrosidase gene (GBA), causing storage of glucosylceramide in reticuloendothelial cells in multiple organs. Traditionally, the prediction of the phenotype based on the genotype has been reported to be limited. SUBJECTS AND METHODS: We investigated the correlation between the enzymatic residual activity (ERA) and the phenotype at diagnosis of the disease in 45 GD Spanish patients (44 with type I and 1 with type III GD)...
July 2016: QJM: Monthly Journal of the Association of Physicians
https://www.readbyqxmd.com/read/26691915/endoplasmic-reticulum-and-lysosomal-ca%C3%A2-%C3%A2-%C2%BA-stores-are-remodelled-in-gba1-linked-parkinson-disease-patient-fibroblasts
#19
Bethan S Kilpatrick, Joana Magalhaes, Michelle S Beavan, Alisdair McNeill, Matthew E Gegg, Michael W J Cleeter, Duncan Bloor-Young, Grant C Churchill, Michael R Duchen, Anthony H Schapira, Sandip Patel
Mutations in β-glucocerebrosidase (encoded by GBA1) cause Gaucher disease (GD), a lysosomal storage disorder, and increase the risk of developing Parkinson disease (PD). The pathogenetic relationship between the two disorders is unclear. Here, we characterised Ca(2+) release in fibroblasts from type I GD and PD patients together with age-matched, asymptomatic carriers, all with the common N370S mutation in β-glucocerebrosidase. We show that endoplasmic reticulum (ER) Ca(2+) release was potentiated in GD and PD patient fibroblasts but not in cells from asymptomatic carriers...
January 2016: Cell Calcium
https://www.readbyqxmd.com/read/26690983/conformationally-locked-c-glycosides-tuning-aglycone-interactions-for-optimal-chaperone-behaviour-in-gaucher-fibroblasts
#20
C D Navo, F Corzana, E M Sánchez-Fernández, J H Busto, A Avenoza, M M Zurbano, E Nanba, K Higaki, C Ortiz Mellet, J M García Fernández, J M Peregrina
A series of conformationally locked C-glycosides based on the 3-aminopyrano[3,2-b]pyrrol-2(1H)-one (APP) scaffold has been synthesized. The key step involved a totally stereocontrolled C-Michael addition of a serine-equivalent C-nucleophile to tri-O-benzyl-2-nitro-D-galactal, previously published by the authors. Stereoselective transformations of the Michael adduct allowed us the synthesis of compounds with mono- or diantennated aglycone moieties and different topologies. In vitro screening showed highly selective inhibition of bovine liver β-glucosidase/β-galactosidase and specific inhibition of human β-glucocerebrosidase among lysosomal glycosidases for compounds bearing palmitoyl chains in the aglycone, with a marked dependence of the inhibition potency upon their number and location...
January 28, 2016: Organic & Biomolecular Chemistry
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