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

Autor: Yang Z; The Second Affiliated Hospital, Zhejiang University School of Medicine and Liangzhu Laboratory, Zhejiang University, Hangzhou, China., Tao P; The Second Affiliated Hospital, Zhejiang University School of Medicine and Liangzhu Laboratory, Zhejiang University, Hangzhou, China., Han X; The Second Affiliated Hospital, Zhejiang University School of Medicine and Liangzhu Laboratory, Zhejiang University, Hangzhou, China., Kozlova A; Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation, Moscow, Russia., He T; Shenzhen Children's Hospital, Shenzhen, China., Volchkov E; Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation and Peoples' Friendship University of Russia (RUDN University), Moscow, Russia., Nesterenko Z; Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation, Moscow, Russia., Pershin D; Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation, Moscow, Russia., Raykina E; Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation, Moscow, Russia., Fatkhudinov T; Peoples' Friendship University of Russia (RUDN University) and Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution 'Petrovsky National Research Centre of Surgery', Moscow, Russia., Korobeynikova A; Peoples' Friendship University of Russia (RUDN University), Moscow, and Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia., Aksentijevich I; National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland., Yang J; Shenzhen Children's Hospital, Shenzhen, China., Shcherbina A; Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation, Moscow, Russia., Zhou Q; The Second Affiliated Hospital, Zhejiang University School of Medicine and Liangzhu Laboratory, Zhejiang University, Hangzhou, China., Yu X; The Second Affiliated Hospital, Zhejiang University School of Medicine and Liangzhu Laboratory, Zhejiang University, Hangzhou, China.
Jazyk: angličtina
Zdroj: Arthritis & rheumatology (Hoboken, N.J.) [Arthritis Rheumatol] 2024 Nov; Vol. 76 (11), pp. 1670-1678. Date of Electronic Publication: 2024 Aug 06.
DOI: 10.1002/art.42948
Abstrakt: Objective: Autoinflammation 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.
Methods: Whole-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.
Results: We 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 Ca 2+ 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.
Conclusion: Our 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.
(© 2024 American College of Rheumatology.)
Databáze: MEDLINE
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