Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation

Last update 08 May 2025

Basic Info

Synonyms

APLAID, APLAID - autoinflammation phospholipase C gamma 2 associated antibody deficiency and immune dysregulation, AUTOINFLAMMATION, ANTIBODY DEFICIENCY, AND IMMUNE DYSREGULATION

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Introduction

A mixed autoinflammatory and autoimmune syndrome disorder with characteristics of recurrent neutrophilic blistering skin lesions, arthralgia, ocular inflammation, inflammatory bowel disease, absence of autoantibodies, and mild immunodeficiency manifested by recurrent sinopulmonary infections and deficiency of circulating antibodies. Inflammatory phenotype is not provoked by cold temperatures. Caused by heterozygous mutation in the PLCG2 gene on chromosome 16q.

100 Clinical Results associated with Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation

100 Translational Medicine associated with Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation

0 Patents (Medical) associated with Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation

Literatures (Medical) associated with Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation

01 Mar 2025·Journal of Allergy and Clinical Immunology

Splice site and de novo variants can cause PLCG2-associated immune dysregulation with cold urticaria

Article

Author: Oler, Andrew J ; Chou, Sophia R ; Bailey, Alexis C ; Ombrello, Michael J ; Milner, Joshua D ; Baysac, Kathleen

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 classified by mutational effect. PLAID with cold urticaria (PLAID-CU) is caused by in-frame deletions of PLCG2 that are dominant negative at physiologic temperatures but become spontaneously active at subphysiologic temperatures.OBJECTIVEWe identified genetic lesions that cause PLAID by combining RNA sequencing of full-length PLCG2 with whole genome sequencing.METHODSWe studied 9 probands with antibody deficiency and a positive evaporative cooling test, along with 2 known PLAID-CU patients and 3 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. Extracellular signal-regulated kinase (ERK) phosphorylation was quantified by flow cytometry with and without B-cell receptor crosslinking.RESULTSTwo probands expressed novel alternative transcripts of PLCG2 with in-frame deletions. Proband 1, expressing PLCG2 without exons 18-19, carried a splice site mutation in intron 19. Proband 2, expressing PLCG2 without exons 19-22, carried a 14 kb de novo deletion of PLCG2. DT40 cells overexpressing the exon 18-19 or exon 19-22 deletions failed to phosphorylate ERK in response to B-cell receptor crosslinking.CONCLUSIONIn addition to autosomal dominant genomic deletions, de novo deletions and splice site mutations of PLCG2 can also cause PLAID-CU. All of these can be identified by cDNA-based sequencing.

01 Dec 2024·Journal of Allergy and Clinical Immunology

PLCG2 variants in cherubism

Article

Author: Bustamante, Daniel ; Eisig, Sidney B ; Ombrello, Michael J ; Gudis, David A ; Chung, Wendy K ; Chester, Jennifer G ; Carcamo, Benjamin ; Milner, Joshua D

BACKGROUNDCherubism is most commonly caused by rare heterozygous gain-of-function (GOF) missense variants in SH3BP2, which appear to signal through phospholipase C gamma 2 (PLCG2) to cause excessive osteoclast activity leading to expansile lesions in facial bones in childhood. GOF variants in PLCG2 lead to autoinflammatory PLCG2-associated antibody deficiency and immune dysregulation (autoinflammatory PLAID, or PLAID-GOF), characterized by variably penetrant autoinflammatory, autoimmune, infectious, and atopic manifestations. Cherubism has not been reported in PLAID to date.OBJECTIVEWe determined whether GOF PLCG2 variants may be associated with cherubism.METHODSClinical, laboratory, and genomic data from 2 patients with cherubism and other clinical symptoms observed in patients with PLCG2 variants were reviewed. Primary B-cell receptor-induced calcium flux was assessed by flow cytometry.RESULTSTwo patients with lesions consistent with cherubism but no SH3BP2 variants were found to have rare PLCG2 variants previously shown to be GOF in vitro, leading to increased primary B-cell receptor-induced calcium flux in one patient's B cells. Variable humoral defects, autoinflammatory rash, and other clinical and laboratory findings consistent with PLAID were observed as well.CONCLUSIONGOF PLCG2 variants likely represent a novel genetic driver of cherubism and should be assessed in SH3BP2-negative cases. Expansile bony lesions expand the phenotypic landscape of autoinflammatory PLAID, and bone imaging should be considered in PLAID patients.

01 Nov 2024·Arthritis & Rheumatology

Characterization of a Novel Pathogenic PLCG2 Variant Leading to APLAID Syndrome Responsive to a TNF Inhibitor

Article

Author: Han, Xu ; Zhou, Qing ; Aksentijevich, Ivona ; Volchkov, Egor ; Korobeynikova, Anastasia ; Nesterenko, Zoya ; Shcherbina, Anna ; He, Tingyan ; Yang, Zhaohui ; Raykina, Elena ; Yang, Jun ; Yu, Xiaomin ; Pershin, Dmitryi ; Tao, Panfeng ; Kozlova, Anna ; Fatkhudinov, Timur

ObjectiveAutoinflammation and phospholipase C (PLC) γ2–associated antibody deficiency and immune dysregulation (APLAID) syndrome is an autoinflammatory disease caused by gain‐of‐function variants in PLCG2. This study investigates the pathogenic mechanism of a novel variant of PLCG2 in a patient with APLAID syndrome.MethodsWhole‐exome sequencing and Sanger sequencing were used to identify the pathogenic variant in the patient. Single‐cell RNA sequencing, immunoblotting, luciferase assay, inositol monophosphate enzyme‐linked immunosorbent assay, calcium flux assay, quantitative PCR, and immunoprecipitation were used to define inflammatory signatures and evaluate the effects of the PLCG2 variant on protein functionality and immune signaling.ResultsWe identified a novel de novo variant, PLCG2 p.D993Y, in a patient with colitis, pansinusitis, skin rash, edema, recurrent respiratory infections, B‐cell deficiencies, and hypogammaglobulinemia. The single‐cell transcriptome revealed exacerbated inflammatory responses in the patient's peripheral blood mononuclear cells. Expression of the D993Y variant in HEK293T, COS‐7, and PLCG2 knock‐out THP‐1 cell lines showed heightened PLCγ2 phosphorylation; elevated inositol‐1,4,5‐trisphosphate production and intracellular Ca2+ release; and activation of the MAPK, NF‐κB, and NFAT signaling pathways compared with control‐transfected cells. In vitro experiments indicated that the D993Y variant altered amino acid properties, disrupting the interaction between the catalytic and autoinhibitory domains of PLCγ2, resulting in PLCγ2 autoactivation.ConclusionOur findings demonstrated that the PLCG2 D993Y variant is a gain‐of‐function mutation via impairing its autoinhibition, activating multiple inflammatory signaling pathways, thus leading to APLAID syndrome. This study further broadens the molecular underpinnings and phenotypic spectrum of PLCγ2‐related disorders.

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Autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation

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