The Influence of Genetic Variability and Proinflammatory Status on the Development of Bone Disease in Patients with Gaucher Disease

Gervas-Arruga, Javier; Cebolla, Jorge J.; Blas, Ignacio de; Roca, Montserrat; Pocovı́, Miguel; Giraldo, Pilar

doi:10.1371/journal.pone.0126153

Cited by 28 publications

(34 citation statements)

References 43 publications

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“…in VDR, finding that they were associated with protection from loss of bone mineral density in splenectomized patients with GD. These results indicate that genetic variability contributes to susceptibility to bone disease in GD (Gervas-Arruga et al, 2015).…”

Section: Bone Diseasementioning

confidence: 62%

“…Moreover, Gervas‐Arruga et al., studied polymorphic sites in three genes, specifically rs2234693 in ESRI (estrogen receptor 1), rs2073618 in TNFRSF11B (TNF‐receptor superfamily member 11b) and rs11868820 in VDR , finding that they were associated with protection from loss of bone mineral density in splenectomized patients with GD. These results indicate that genetic variability contributes to susceptibility to bone disease in GD (Gervas‐Arruga et al., ).…”

Section: Modifiers May Mediate Other Gaucher‐associated Disordersmentioning

confidence: 83%

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Exploring genetic modifiers of Gaucher disease: The next horizon

et al. 2018

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Gaucher disease is an autosomal recessive lysosomal storage disorder resulting from mutations in the gene GBA1 that lead to a deficiency in the enzyme glucocerebrosidase. Accumulation of the enzyme's substrates, glucosylceramide and glucosylsphingosine, results in symptoms ranging from skeletal and visceral involvement to neurological manifestations. Nonetheless, there is significant variability in clinical presentations amongst patients, with limited correlation between genotype and phenotype. Contributing to this clinical variation are genetic modifiers that influence the phenotypic outcome of the disorder. In this review, we explore the role of genetic modifiers in Mendelian disorders and describe methods to facilitate their discovery. In addition, we provide examples of candidate modifiers of Gaucher disease, explore their relevance in the development of potential therapeutics, and discuss the impact of GBA1 and modifying mutations on other more common diseases like Parkinson disease. Identifying these important modulators of Gaucher phenotype may ultimately unravel the complex relationship between genotype and phenotype and lead to improved counseling and treatments.

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Section: Bone Diseasementioning

confidence: 62%

Section: Modifiers May Mediate Other Gaucher‐associated Disordersmentioning

confidence: 83%

Exploring genetic modifiers of Gaucher disease: The next horizon

et al. 2018

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“…In fact, a homozygous mutation in human β-glucocerebrosidase (GBA1), a crucial enzyme degrading β-GlcCer, leads to Gaucher disease because of a reduction in enzyme activity that causes accumulation of β-GlcCer (19). Gaucher disease is characterized by systemic inflammation, which presents hepatosplenomegaly or neurodegeneration (20)(21)(22)(23)(24). However, the molecular mechanisms that link excessive β-GlcCer to inflammatory responses are not yet understood.…”

mentioning

confidence: 99%

Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

Nagata

Izumi

Ishikawa

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

147

126

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Sensing and reacting to tissue damage is a fundamental function of immune systems. Macrophage inducible C-type lectin (Mincle) is an activating C-type lectin receptor that senses damaged cells. Notably, Mincle also recognizes glycolipid ligands on pathogens. To elucidate endogenous glycolipids ligands derived from damaged cells, we fractionated supernatants from damaged cells and identified a lipophilic component that activates reporter cells expressing Mincle. Mass spectrometry and NMR spectroscopy identified the component structure as β-glucosylceramide (GlcCer), which is a ubiquitous intracellular metabolite. Synthetic β-GlcCer activated myeloid cells and induced production of inflammatory cytokines; this production was abrogated in Mincle-deficient cells. Sterile inflammation induced by excessive cell death in the thymus was exacerbated by hematopoietic-specific deletion of degrading enzyme of β-GlcCer (β-glucosylceramidase, GBA1). However, this enhanced inflammation was ameliorated in a Mincle-deficient background. GBA1-deficient dendritic cells (DCs) in which β-GlcCer accumulates triggered antigen-specific T-cell responses more efficiently than WT DCs, whereas these responses were compromised in DCs from GBA1 × Mincle double-deficient mice. These results suggest that β-GlcCer is an endogenous ligand for Mincle and possesses immunostimulatory activity.

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“…20,21 To maintain the delicate balance in the bone environment, the final phase of osteoblast differentiation is believed to be carefully controlled 22 as osteoblasts are responsible for stimulating osteoclast differentiation. 23 Studies in osteoimmunology describe this process as a complex interaction between bone cell development and immune cells, and point to activated T-cells as key players in this involvement, given their production of a number of inflammatory cytokines 24 either directly or indirectly regulating the cells involved in the bone turnover balance -shifting in either direction, bone reabsorption or bone generation.…”

Section: Pathophysiology Of Skeletal Manifestationsmentioning

confidence: 99%

“…But as the field of genetics advances, we are becoming even more mindful of the complexity, due to modifier genes, gene polymorphisms and other factors influencing the rampant phenotypic variability. 21 Despite these complexities, the field is advancing, and will usher in even earlier identification, offering hope in making truly impactful management of the manifestations of GD.…”

Section: Underlying Pathophysiologymentioning

confidence: 99%

Doença De Gaucher Tipo 1 No Esqueleto: Revisão Da América Latina

2016

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Gaucher disease (GD) is the most prevalent lysosomal storage disease, and is characterized by the accumulation of glucosylceramide and glucosylsphingosine in tissues throughout the body. With the advent of enzyme replacement therapy, the prognosis for patients with GD has dramatically improved. Still, the skeletal manifestations associated with GD respond slowly to enzyme replacement therapy and are the most significant contributor of disease related patient morbidity. This review of bone manifestations in GD presents the most recent theories on its pathophysiology, and gives a systematic review of studies with Latin American patients that report the frequency of bone manifestations and the effects of enzyme replacement therapy on their treatment. We conclude by emphasizing the importance of early identification and proper management at appropriate dosage levels of enzyme replacement therapy to reduce the morbidity caused by GD.Keywords: Gaucher disease; Skeleton; Prevalence; Latin America. RESUMO A doença de Gaucher (DG) é a doença de depósito lisossômico mais prevalente, que se caracteriza pelo acúmulo de glicosilceramida e glucosilesfingosina em todos os tecidos do corpo. Com o advento da terapia de reposição de enzimas, o prognóstico dos pacientes com DG melhorou acentuadamente. Ainda assim, as manifestações esqueléticas associadas à DG respondem lentamente à terapia de reposição de enzimas e são as que contribuem de forma mais significativa para a morbidade do paciente. Esta revisão das manifestações ósseas da DG apresenta as mais recentes teorias sobre a sua fisiopatologia e uma revisão sistemática de estudos com pacientes latino-americanos que relataram a frequência das manifestações ósseas e os efeitos da terapia de reposição de enzimas

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The Influence of Genetic Variability and Proinflammatory Status on the Development of Bone Disease in Patients with Gaucher Disease

Cited by 28 publications

References 43 publications

Exploring genetic modifiers of Gaucher disease: The next horizon

Exploring genetic modifiers of Gaucher disease: The next horizon

Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity

Doença De Gaucher Tipo 1 No Esqueleto: Revisão Da América Latina

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