Gene-specific RNA sequencing in PLCG2-associated immune dysregulation with cold urticaria
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1171025 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:BACKGROUND:Mendelian analysis of disorders of immune regulation can provide insight into molecular pathways associated with host defense and immune tolerance. METHODS:We identified three families with a dominantly inherited complex of cold-induced urticaria, antibody deficiency, and susceptibility to infection and autoimmunity. Immunophenotyping methods included flow cytometry, analysis of serum immunoglobulins and autoantibodies, lymphocyte stimulation, and enzymatic assays. Genetic studies included linkage analysis, targeted Sanger sequencing, and next-generation whole-genome sequencing. RESULTS:Cold urticaria occurred in all affected subjects. Other, variable manifestations included atopy, granulomatous rash, autoimmune thyroiditis, the presence of antinuclear antibodies, sinopulmonary infections, and common variable immunodeficiency. Levels of serum IgM and IgA and circulating natural killer cells and class-switched memory B cells were reduced. Linkage analysis showed a 7-Mb candidate interval on chromosome 16q in one family, overlapping by 3.5 Mb a disease-associated haplotype in a smaller family. This interval includes PLCG2, encoding phospholipase C?(2) (PLC?(2)), a signaling molecule expressed in B cells, natural killer cells, and mast cells. Sequencing of complementary DNA revealed heterozygous transcripts lacking exon 19 in two families and lacking exons 20 through 22 in a third family. Genomic sequencing identified three distinct in-frame deletions that cosegregated with disease. These deletions, located within a region encoding an autoinhibitory domain, result in protein products with constitutive phospholipase activity. PLCG2-expressing cells had diminished cellular signaling at 37°C but enhanced signaling at subphysiologic temperatures. CONCLUSIONS:Genomic deletions in PLCG2 cause gain of PLC?(2) function, leading to signaling abnormalities in multiple leukocyte subsets and a phenotype encompassing both excessive and deficient immune function. (Funded by the National Institutes of Health Intramural Research Programs and others.).
| S-EPMC3298368 | biostudies-literature
Project description:BackgroundPhospholipase Cγ2 (PLCγ2) is an important signaling molecule that receives and transmits signals from various cell surface receptors in most hematopoietic lineages. Variants of PLCG2 cause PLCγ2-associated immune dysregulation (PLAID), a family of conditions that are classified by mutational effect. PLAID with cold urticaria (CU-PLAID) is caused by in-frame deletions of PLCG2 that are dominant negative at physiologic temperatures but become spontaneously active at sub-physiologic temperatures.ObjectiveTo identify genetic lesions that cause PLAID by combining RNA sequencing of full-length PLCG2 with whole genome sequencing.MethodsWe studied nine probands with antibody deficiency and a positive evaporative cooling test, together with two known CU-PLAID patients and three healthy subjects. Illumina sequencing was performed on full-length PLCG2 cDNA synthesized from peripheral blood mononuclear cell RNA and whole genome sequencing was used to identify genetic lesions. Novel alternate transcripts were overexpressed in the Plcg2-deficient DT40 cell overexpression system. ERK phosphorylation was quantified by flow cytometry with and without BCR crosslinking.ResultsTwo probands expressed novel alternative transcripts of PLCG2 with in-frame deletions. The first, expressing PLCG2 without exons 18-19, carried a splice site mutation in intron 19. The second, expressing PLCG2 without exons 19-22, carried a 14kb de novo deletion of PLCG2. DT40 cells overexpressing the exon 18-19 or exon 19-22 deletions failed to phosphorylate ERK in response to BCR crosslinking.ConclusionIn addition to autosomal dominant genomic deletions, de novo deletions and splice site mutations of PLCG2 can also cause CU-PLAID. All of these can be identified by cDNA-based sequencing.
| S-EPMC10984065 | biostudies-literature
Project description:Human genetic studies have pointed to a prominent role for innate immunity and lipid pathways in human immunological and neurodegenerative disorders. Our understanding of the composition and function of immunomodulatory lipid networks in innate immune cells, however, remains incomplete. Here, we show that phospholipase C gamma 2 (PLCγ2 or PLCG2) – mutations in which are associated with autoinflammatory disorders and Alzheimer’s disease – serves as a principal source of diacylglycerol (DAG) pools that are converted into a cascade of bioactive endocannabinoid (eCB) and eicosanoid lipids by DAG lipase (DAGL) and monoacylglycerol lipase (MGLL) enzymes in innate immune cells. We show that this lipid network is tonically stimulated by disease-relevant human mutations in PLCγ2, as well as Fc receptor activation in primary human and mouse macrophages. Genetic disruption of PLCγ2 in mouse microglia suppressed DAGL/MGLL-mediated eCB-eicosanoid crosstalk and also caused widespread transcriptional and proteomic changes, including the reorganization of immune-relevant lipid pathways reflected in reductions in DAGLB and elevations in PLA2G4A. Despite these changes, Plcg2-/- mice showed generally normal pro-inflammatory cytokine responses to lipopolysaccharide treatment, instead displaying a more restricted deficit in microglial activation that included impairments in prostaglandin production and CD68 expression. Our findings enhance the understanding of PLCγ2 function in innate immune cells, delineating a role in crosstalk with endocannabinoid/eicosanoid pathways and modulation of subsets of cellular responses to inflammatory stimuli.
2021-10-05 | PXD027350 | Pride
Project description:Lesions of chronic idiopathic urticaria (CIU) showed significant up-regulation of 506 genes and reduced expression of 51 genes.
2014-08-12 | GSE57178 | GEO
Project description:Human genetic studies have pointed to a prominent role for innate immunity and lipid pathways in human immunological and neurodegenerative disorders. Our understanding of the composition and function of immunomodulatory lipid networks in innate immune cells, however, remains incomplete. Here, we show that phospholipase C gamma 2 (PLCγ2 or PLCG2) – mutations in which are associated with autoinflammatory disorders and Alzheimer’s disease – serves as a principal source of diacylglycerol (DAG) pools that are converted into a cascade of bioactive endocannabinoid (eCB) and eicosanoid lipids by DAG lipase (DAGL) and monoacylglycerol lipase (MGLL) enzymes in innate immune cells. We show that this lipid network is tonically stimulated by disease-relevant human mutations in PLCγ2, as well as Fc receptor activation in primary human and mouse macrophages. Genetic disruption of PLCγ2 in mouse microglia suppressed DAGL/MGLL-mediated eCB-eicosanoid crosstalk and also caused widespread transcriptional and proteomic changes, including the reorganization of immune-relevant lipid pathways reflected in reductions in DAGLB and elevations in PLA2G4A. Despite these changes, Plcg2-/- mice showed generally normal pro-inflammatory cytokine responses to lipopolysaccharide treatment, instead displaying a more restricted deficit in microglial activation that included impairments in prostaglandin production and CD68 expression. Our findings enhance the understanding of PLCγ2 function in innate immune cells, delineating a role in crosstalk with endocannabinoid/eicosanoid pathways and modulation of subsets of cellular responses to inflammatory stimuli.
2021-10-04 | GSE180274 | GEO
Project description:Differential expression analysis in Plcg2-inactivated mouse model identified inflammation-related genes and pathways.
2022-02-07 | GSE195650 | GEO
Project description:PLCG2 regulates endocannabinoid and eicosanoid networks in innate immune cells
| PRJNA747300 | ENA
Project description:Differential expression analysis identified inflammation-related pathways in AD samples with reduced PLCG2 expression
2025-01-01 | GSE196502 | GEO
Project description:Chronic spontaneous urticaria (CSU), also traditionally called Chronic Idiopathic Urticaria (CIU), is a common dermatosis. Its estimated point prevalence is 0.6 to 1%. CSU is defined by spontaneously occurring short-lived and itching wheal, angioedema or both. The current nomenclature of urticaria endorses the use of a clinical rather than an aetiological classification to recognise that a percentage of patients with CSU have an autoimmune rather than idiopathic aetiology. As it happens with other IgE-associated diseases, a better knowledge of urticaria patients requires defining phenotypes. The present knowledge about CSU phenotypes is based on the clinical characteristics, associated comorbidities, the course of the disease and its response to the available effective drugs. But a phenotype is defined as the visible characteristics or traits that are a consequence of the expression of genes as well as the influence of environmental factors. The phenotype is part a consequence of the genotype. To study which is the genotype expressed by the patients suffering of CSU can be interesting. The mechanisms involved in the mast cell activation and the role of the released mast cell mediators are well known allowing explaining of how the wheals appear and disappear. But very little is known about the genetic susceptibility and genes involved in the development of wheals in CSU patients. By means of this work, enough case series was collected to draw reliable conclusions, based on the genetic variations found. In order to assess associations between genetic polymorphisms and the different phenotypes of CSU, large case series of well-documented patients with a relevant history are needed. The primary purpose of this study was to identify the most relevant genes expressed in the tissue and the blood samples from patients with moderate and severe CSU.
2017-04-19 | GSE72541 | GEO
Project description:Chronic spontaneous urticaria (CSU), also traditionally called Chronic Idiopathic Urticaria (CIU), is a common dermatosis. Its estimated point prevalence is 0.6 to 1%. CSU is defined by spontaneously occurring short-lived and itching wheal, angioedema or both. The current nomenclature of urticaria endorses the use of a clinical rather than an aetiological classification to recognise that a percentage of patients with CSU have an autoimmune rather than idiopathic aetiology. As it happens with other IgE-associated diseases, a better knowledge of urticaria patients requires defining phenotypes. The present knowledge about CSU phenotypes is based on the clinical characteristics, associated comorbidities, the course of the disease and its response to the available effective drugs. But a phenotype is defined as the visible characteristics or traits that are a consequence of the expression of genes as well as the influence of environmental factors. The phenotype is part a consequence of the genotype. To study which is the genotype expressed by the patients suffering of CSU can be interesting. The mechanisms involved in the mast cell activation and the role of the released mast cell mediators are well known allowing explaining of how the wheals appear and disappear. But very little is known about the genetic susceptibility and genes involved in the development of wheals in CSU patients. By means of this work, enough case series was collected to draw reliable conclusions, based on the genetic variations found. In order to assess associations between genetic polymorphisms and the different phenotypes of CSU, large case series of well-documented patients with a relevant history are needed. The primary purpose of this study was to identify the most relevant genes expressed in the tissue and the blood samples from patients with moderate and severe CSU.
2017-04-19 | GSE72540 | GEO