A mutation in PIK3CD gene causing pediatric systemic lupus erythematosus

Li, Guomin; Liu, Haimei; Guan, Wanzhen; Xu, Hong; Wu, Bingbing; Feng, Juan; Sun, Li

doi:10.1097/md.0000000000015329

Cited by 14 publications

(11 citation statements)

References 21 publications

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“…The de novo mutation, c.3061G>A (p.E1021K) in PIK3CD gene, was detected in patient 6, also reported in previously our study [23] . Gain of function (GOF) mutations in PIK3CD gene, encoding PI3K p110δ, were recently associated with a novel combined immune deficiency characterized by recurrent sinopulmonary infections, reduced class-switched memory B cells, lymphadenopathy, CD4 + lymphopenia, CMV and/or EBV viremia and EBV-related lymphoma [24,25] .…”

Section: Discussionsupporting

confidence: 87%

Genetic heterogeneity of pediatric systemic lupus erythematosus with lymphoproliferation

Liu

et al. 2019

Preprint

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Purpose: Systemic lupus erythematosus (SLE) is a rare autoimmune disease, which is more severe in case of pediatric onset. This may be due to greater involvement of genetic factors compared with adult forms. In recent years, multiple monogenic diseases with early-onset autoimmunity and lymphoproliferation have been identified, such as Autoimmune lymphoproliferative syndrome (ALPS), RAS-associated autoimmune leukoproliferative disease (RALD), Signal transducer and activator of transcription 3 (STAT3) Gain-of-Function (GOF) syndrome and Interleukin-2 receptor α (IL2RA) deficiency. Therefore, we performed whole exome sequencing in SLE children with lymphoproliferation to identify genes associated with these conditions. Methods: We enrolled seven SLE patients with lymphoproliferation, which are from different families. Demographic data, clinical manifestations, laboratory and histopathological findings, treatment, and outcome were documented. WES was performed in seven cases and their families. Suspected variants were confirmed by Sanger sequencing. Protein levels were detected in patients with gene mutations by Western blot. Results: Four patients were male, and three were female. No consanguinity was reported within the seven families. The average age at onset was 5.0 years (range from 1.2 to 10.0 years). The most common features were renal (7/7 patients), hematological (6/7 patients) involvement, and recurrent fever (6/7patients) while only two patients presented with skin involvement. Antinuclear antibodies ( ANA) at a titer of ≥1:320 was positive in all patients. All patients fulfilled four 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) criteria for the classification of SLE. We identified a somatic activating NRAS variant (c.38 A>G, p.G13C) in peripheral venous blood from four patients, at levels ranging from 8.8% to 42.8% in variant tissues, that was absent from their parents. BCL-2-Interacting Mediator of Cell Death (BIM) levels in peripheral blood mononuclear cells (PBMCs) from four patients were markedly reduced, whereas those in control was normal. Another two mutations, c.559C>T (p.Q187X) in the TNFAIP3 gene and c.3061G>A (p.E1021K) in PIK3CD gene, were detected in two patients, respectively. Conclusion: SLE is a novel phenotype of germline mutation in PI3CKD gene and somatic mutation in NRAS gene. These genes, NRAS , TNFAIP3 and PIK3CD , should be considered as candidates for SLE children with lymphoproliferation. If patients with SLE and lymphoproliferation presented with renal and hematological involvement, and recurrent fever, they need gene testing, especially in male patient.

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Section: Discussionsupporting

confidence: 87%

Genetic heterogeneity of pediatric systemic lupus erythematosus with lymphoproliferation

Liu

et al. 2019

Preprint

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“…It was reported that mutation of gene pik3cd was associated with the prevalence of systemic lupus erythematosus, which is a typical immune system disease [41]. Hence, the marked increase of the mRNA level of pik3cd in lung tissue from exposure group might related to the immune response induced by PM 2.5 .…”

Section: Discussionmentioning

confidence: 94%

Assessment on the lung injury of mice posed by airborne PM2.5 collected from developing area in China and associated molecular mechanisms: from histopathology to integrated transcriptome analysis

Dai

Yang

et al. 2020

Preprint

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Background & aimsSome epidemiological investigations have revealed airborne fine particulate matter (PM2.5) could induce adverse effects on respiratory system of human. However, the experimental evidences of the harmful effect of PM2.5 from mid-scale city in China and associated molecular mechanisms was still scarce. In this study, we aimed to evaluate the adverse effect on the lung system of PM2.5 collected from mid-city of China and elucidate the underlying molecular mechanism through mRNA-seq and microRNA-seq integrated analysis.MethodsWe exposed male Balb/C mice to PM2.5 collected from Baoji city, China for 8 weeks (298.52 ± 25.86 μg/m3) using a whole-body exposure system. Micro-CT and histopathological analyses were performed to determine the morphology and histopathology changes of lung tissues induced by PM2.5. Transcriptome (both mRNA and microRNA) sequencing and the immunohistochemistry assay were performed to reveal the associated underlying mechanisms. The contents of PAHs absorbed in the PM2.5, as well as the pearson correlation index between it and the target genes and microRNA were examined.ResultsObvious lung injury including pulmonary dysfunction, immunological responses, and fibrosis were observed from the PM2.5 exposure group. The content of leucocyte of lung tissue was significantly increased. PM2.5 mainly induced immune pathways including B cell receptor signaling and cell adhesion molecules (CAMs). The expression levels of the associated genes and microRNA were verified using RT-qPCR. The protein expression of CD19, CD81, and PIK3CD involved into B cell receptor signaling significantly increased in exposure group. The concentrations of benzo(a)pyrene (BaP) showed a marked correlationship with the genes and microRNA. ConclusionsPM2.5 from the mid-scale city of China caused adverse effects on lung system of mice, which was much stronger than the mega city, indicating the health risk of the air pollution in the developing area should be paid more attention. The toxicity of PM2.5 may associated with immune system response. This work for the first time provided a new sight into the molecular mechanism of PM2.5 toxicity on lung system using transcriptomics integrated analysis and help further to develop effective measures to prevent air pollution associated lung disease, especially in the developing area in China.

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“…However, glomerulonephritis and lupus-like nephritis have previously been described [ 3 ]. There was one case of a child with PIK3δ who also met criteria for systemic lupus erythematosus based on persistent proteinuria and hematuria, among other findings [ 11 ]. In a murine model, PI3Kδ inhibition reduced macrophage infiltration of the kidney by diminishing the macrophage’s ability to cross the basement membrane [ 12 ]; if PI3Kδ were overactive, macrophages may infiltrate renal tissue more readily, leading to nephromegaly.…”

Section: Discussionmentioning

confidence: 99%

Activated phosphoinositide 3-kinase δ syndrome associated with nephromegaly, growth hormone deficiency, bronchiectasis: a case report

Craig

Geng

Wigby

et al. 2022

Allergy Asthma Clin Immunol

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Background Activated phosphoinositide 3-kinase (PI3K) δ syndrome (APDS) is a rare form of primary immunodeficiency with 243 known cases reported in the literature. Known findings associated with the condition include recurrent sinusitis and bronchitis, bronchiectasis, immune cytopenias, mild developmental delay, splenomegaly, and lymphadenopathy. We report the case of a child with APDS accompanied by unique clinical features: nephromegaly and growth hormone deficiency with associated pituitary anatomic abnormality. Case presentation The patient is a nine-year-old boy with a heterozygous de novo variant in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit δ (p.E1021K), previously reported in association with APDS. Our patient, who had no family history of immunodeficiency, exhibits classic findings of this syndrome but also has unique features that extend the phenotypic spectrum of this disorder. At 5 years of age, the patient showed marked growth deceleration and was demonstrated to have growth hormone (GH) deficiency with associated pituitary anatomic abnormality. He started GH therapy with an excellent response. He additionally has bilateral nephromegaly of unclear etiology, microscopic hematuria and proteinuria, asthma, and has developed left hip pain with arthrocentesis consistent with oligoarticular juvenile idiopathic arthritis. At age nine, the patient was referred to genetics and whole exome sequencing revealed APDS. Though there was initial concern that GH may increase risk for malignancy as GH signals through the PI3K pathway, he was allowed to continue treatment as the PI3K pathway was considered constitutively active at baseline. Conclusions Our patient’s unique presentation adds to the clinical information regarding APDS, demonstrates the utility of genetic testing and illustrates the importance of a multidisciplinary collaborative approach in managing this complex syndrome.

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A mutation in PIK3CD gene causing pediatric systemic lupus erythematosus

Cited by 14 publications

References 21 publications

Genetic heterogeneity of pediatric systemic lupus erythematosus with lymphoproliferation

Genetic heterogeneity of pediatric systemic lupus erythematosus with lymphoproliferation

Assessment on the lung injury of mice posed by airborne PM2.5 collected from developing area in China and associated molecular mechanisms: from histopathology to integrated transcriptome analysis

Activated phosphoinositide 3-kinase δ syndrome associated with nephromegaly, growth hormone deficiency, bronchiectasis: a case report

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