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          NIAMS Scientific Advances
          Genetic Variants of PLCG2 Cause Immune Dysregulation Through Either Increased or Decreased Function








NIAMS Advances


Genetic Variants of PLCG2 Cause Immune Dysregulation Through Either Increased or Decreased Function September 26, 2023
                                CLINICAL
        Michael J. Ombrello, M.D.
                                          |
              Translational Genetics and Genomics Section
                                          |
              NIAMS IRP
        Description*PLCG2* variants are frequently detected in people with immune dysregulation, but whether individual variants cause or contribute to immune abnormalities is unknown. Dominant variants of *PLCG2* in humans lead to aberrant leukocyte signaling with variably expressed symptoms that include low serum immunoglobulin levels, recurrent sinopulmonary infections, autoimmunity-related cold rash, and sterile inflammation. In this study, the researchers used an in vitro approach to characterize the effects of 60 *PLCG2* variants of uncertain significance identified in a group of 76 people with immune dysregulation. Over 70% of the variants result in PLCG2-dependent altered function, and most of the variants led to reduced PLCG2 activity, which suggests a new class of *PLCG2* mutation and a novel form of PLCG2-associated immune dysregulation.What is exciting about this article?This study of people with immune dysregulation and PLCG2 variants suggests for the first time that genetic variants of PLCG2 that reduce its functional capacity can cause an autosomal dominant form of immune dysregulation. This finding expands our understanding of genotypic and phenotypic PLCG2-associated immune dysregulation. It also highlights the need for more diverse assays to accurately assess cell-type specific effects of *PLCG2* variants on human disease.Grant SupportAR041198
        Research Areas:
            Autoimmunity
      Genetics and Genomics
                                        Reference:
            PLCG2-associated immune dysregulation (PLAID) comprises broad and distinct clinical presentations related to functional classes of genetic variants.

    Baysac K, Sun G, Nakano H, Schmitz EG, Cruz AC, Fisher C, Bailey AC, PLCG2-Immune Dysregulation Working Group, Mace E, Milner JD, Ombrello MJ
        

                    J Allergy Clin Immunol.
        
                    2024 Jan;
        
                    153(1).
        
                    doi: 10.1016/j.jaci.2023.08.036
                            PMID: 37769878
        Research reported in this publication was supported by the Intramural Research Program of the NIHʼs National Institute of Arthritis and Musculoskeletal and Skin Diseases.
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