Characterization of a Novel Pathogenic PLCG2 Variant Leading to APLAID Syndrome Responsive to a TNF inhibitor.
Arthritis Rheumatol
; 2024 Jul 04.
Article
en En
| MEDLINE
| ID: mdl-38965708
ABSTRACT
OBJECTIVE:
Autoinflammation and PLCγ2-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, IP-one ELISA, 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 PBMCs. Expression of the D993Y variant in HEK293T, COS-7, and PLCG2 knock-out THP-1 cell lines showed heightened PLCγ2 phosphorylation, elevated IP3 production and intracellular Ca2+ release, and activation of the MAPK, NFκB, and NFAT signaling pathways compared to control-transfected cells. In vitro experiments indicated that the D993Y variant altered amino acid properties, disrupting the interaction between the catalytic and auto-inhibitory domains of PLCγ2, resulting in PLCγ2 auto-activation.CONCLUSIONS:
Our findings demonstrated that the PLCG2 D993Y variant is a gain-of-function mutation via impairing its auto-inhibition, activating multiple inflammatory signaling pathways, thus leading to APLAID syndrome. This study further broadens the molecular underpinnings and phenotypic spectrum of PLCγ2-related disorders.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Arthritis Rheumatol
Año:
2024
Tipo del documento:
Article
País de afiliación:
China