Biochemical and Molecular Chitotriosidase Profiles in Patients with Gaucher Disease Type 1 in Minas Gerais, Brazil: New Mutation in CHIT1 Gene

Adelino, Talita; Martins, Gustavo G; Gomes, Aretta A A; Torres, A. A. G.; Silva, Daniel A S; Xavier, Vinícius D O; Guimaraes, Joao Paulo O.; Araújo, Sérgio S S; Fernandes, Rachel Aparecida Ferreira; Oliveira, M. C.; Godard, Ana Lúcia Brunialti; Valadares, Eugênia Ribeiro

doi:10.1007/8904_2012_184

Cited by 6 publications

(6 citation statements)

References 39 publications

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“…Clinical and animal studies have suggested that Gaucher macrophages are the source of the elevated levels of cytokines and ChT1 present in patient serum . Our results directly demonstrate that GD hiPSC macrophages are activated, are hypersensitive to the bacterial product LPS, and that they produce increased levels of IL‐1β, TNF‐α, IL‐6, and ChT1.…”

Section: Discussionsupporting

confidence: 61%

“…ChT1, an enzyme produced by macrophages and neutrophils , is highly elevated in symptomatic patients with GD . Serum levels of ChT1 in patients with type 1 GD reflect the burden of lipid‐laden macrophages, and ChT1 is used to help determine the dosing of recombinant GCase and to follow the response to ERT .…”

Section: Resultsmentioning

confidence: 99%

“…Serum levels of ChT1 in patients with type 1 GD reflect the burden of lipid‐laden macrophages, and ChT1 is used to help determine the dosing of recombinant GCase and to follow the response to ERT . IL‐6 and CCL‐18 are also used as biomarkers of GD , particularly in the 6% of the human population harboring a mutation in the ChT1 gene that abrogates its expression . To determine whether GD hiPSC macrophages produce elevated levels of ChT1, we measured ChT1 enzymatic activity in GD hiPSC macrophages.…”

Section: Resultsmentioning

confidence: 99%

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Gaucher iPSC-Derived Macrophages Produce Elevated Levels of Inflammatory Mediators and Serve as a New Platform for Therapeutic Development

et al. 2014

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Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the acid beta-glucocerebrosidase (GBA) gene. The hallmark of GD is the presence of lipid-laden Gaucher macrophages, which infiltrate bone marrow and other organs. These pathological macrophages are believed to be the source of elevated levels of inflammatory mediators present in the serum of GD patients. The alteration in the immune environment caused by GD is believed to play a role in the increased risk of developing multiple myeloma and other malignancies in GD patients. To determine directly whether Gaucher macrophages are abnormally activated and if their functional defects can be reversed by pharmacological intervention, we generated GD macrophages by directed differentiation of human iPS cells (hiPSC) derived from patients with types 1, 2, and 3 GD. GD hiPSC-derived macrophages expressed higher levels of TNF alpha, IL-6, and IL-1beta than control cells, and this phenotype was exacerbated by treatment with LPS. In addition, GD hiPSC macrophages exhibited a striking delay in clearance of phagocytosed red blood cells, recapitulating the presence of RBC remnants in Gaucher macrophages from bone marrow aspirates. Incubation of GD hiPSC macrophages with recombinant glucocerebrosidase, or with the chaperones isofagomine and ambroxol, corrected the abnormal phenotypes of GD macrophages to an extent that reflected their known clinical efficacies. We conclude that Gaucher macrophages are the likely source of the elevated levels of inflammatory mediators in the serum of GD patients, and that GD hiPSC are valuable new tools for studying disease mechanisms and drug discovery.

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Section: Discussionsupporting

confidence: 61%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Gaucher iPSC-Derived Macrophages Produce Elevated Levels of Inflammatory Mediators and Serve as a New Platform for Therapeutic Development

et al. 2014

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“…Initial evaluations of the ethnic Polish Gaucher disease type 3 variants , the Gaucher disease type 1 variants from South America and Japan, and other demographic/ethnic groups have shown the spectra of the major manifestations among and between the populations. The type 1 variants in Brazil , although mostly of European derivation, appear to have more pulmonary and bony involvement than those of North American, European, or Ashkenazi Jewish ancestry. However, the full spectra of ethnic phenotypic variation within and among the Gaucher disease variants will require detailed, longitudinal phenotypic characterizations of large numbers of patients.…”

Section: Introductionmentioning

confidence: 90%

Gaucher disease types 1 and 3: Phenotypic characterization of large populations from the ICGG Gaucher Registry

2015

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Study of the natural history of Gaucher disease has revealed marked phenotypic variation. Correlations to genotypes could provide insight into individual susceptibility to varying disease severity, which may impact whole‐life medical care, reproductive decisions, and therapeutic choices for affected families. Importantly, pre‐symptomatic or prospective interventions or the use of therapies with significant risk require accurate risk‐benefit analyses based on the prognosis for individual patients. The body of international data held within the International Collaborative Gaucher Group (ICGG) Gaucher Registry provides an unprecedented opportunity to characterize the phenotypes of Gaucher disease types 1 and 3 and to appreciate demographic and ethnic factors that may influence phenotypes. The diversity of GBA gene mutations from patients with Gaucher disease represented in the ICGG Gaucher Registry database and in the literature provides the basis for initial genotype/phenotype correlations, the outcomes of which are summarized here.Am. J. Hematol. 90:S12–S18, 2015. © 2015 Wiley Periodicals, Inc.

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“…As expected, subjects carrying exon duplication in homozygosis showed null ChT activity and the heterozygotes subjects showed a significant lower level compared to subjects without the exon duplication. To adjust for genotype, we multiply the ChT activity of heterozygotes by 2 in order to compare both groups, as described in several studies [31][32][33][34].…”

Section: Subjects and Samplesmentioning

confidence: 99%

Evaluation of Chitotriosidase and CC-Chemokine Ligand 18 as Biomarkers of Microglia Activation in Amyotrophic Lateral Sclerosis

et al. 2018

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Background: The development of biomarkers for use in diagnosing, monitoring disease progression and analyzing therapeutic trials response in amyotrophic lateral sclerosis (ALS) is essential. Objective: The aim of this study was to identify inflammatory factors in plasma or cerebrospinal fluid (CSF) from patients with ALS with particular attention to specific markers of microglia activation as chitotriosidase (ChT) and chemokine (C-C motif) ligand 18 (CCL18) to determine its potential as ALS biomarkers. Methods: We studied CSF and plasma samples from 32 patients and 42 healthy controls. We assayed the ChT activity by a spectrofluorometric method and protein levels of other inflammatory biomarkers (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6 and CCL18) by enzyme-linked immunosorbent assay. CHIT1 gene polymorphism in exon 10 (c.1049_1072dup24) encoding inactive ChT enzyme was genotyped in all subjects. Results: ChT activity and TNF-alpha protein levels were significantly higher in CSF of ALS patients, but we found no correlation with the severity and progression of the disease. Nevertheless, we did not found any differences in CCL18 or IL-6 protein levels between both groups in CSF or plasma. In our sample, only 3% of subjects were homozygous carriers for the CHIT1 exon 10 duplication associated with defective enzyme. Conclusions: High ChT activity in CSF of patients with ALS may reflect microglia activation and could be a potential biomarker of the disease. We did not find any significant difference regarding CCL-18, another specific marker of microglia activation that is related with M2-like microglia phenotype. Deepening the understanding of the activation state of microglia (M1 and M2) may contribute to the knowledge about the specific role of neuroinflammation in ALS and future therapeutic strategies.

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Biochemical and Molecular Chitotriosidase Profiles in Patients with Gaucher Disease Type 1 in Minas Gerais, Brazil: New Mutation in CHIT1 Gene

Abstract: Chitotriosidase (ChT)

Cited by 6 publications

References 39 publications

Gaucher iPSC-Derived Macrophages Produce Elevated Levels of Inflammatory Mediators and Serve as a New Platform for Therapeutic Development

Gaucher iPSC-Derived Macrophages Produce Elevated Levels of Inflammatory Mediators and Serve as a New Platform for Therapeutic Development

Gaucher disease types 1 and 3: Phenotypic characterization of large populations from the ICGG Gaucher Registry

Evaluation of Chitotriosidase and CC-Chemokine Ligand 18 as Biomarkers of Microglia Activation in Amyotrophic Lateral Sclerosis

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