Clinical phenotype and immunological features of a patient with A20 haploinsufficiency
10.3760/cma.j.issn.0578-1310.2020.03.011
- VernacularTitle: 新发A20单倍剂量不足一例临床表型及免疫功能研究
- Author:
Yanyan HUANG
1
;
Tingyan HE
2
;
Yu XIA
2
;
Ying LUO
2
;
Ruohang WENG
2
;
Shuli LUO
2
;
Jun YANG
2
;
Xiaodong ZHAO
1
Author Information
1. Department of Rheumatology and Immunology, Children′s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Chongqing 400014, China
2. Department of Rheumatology and Immunology, Shenzhen Children′s Hospital, Shenzhen 518038, China
- Publication Type:Clinical Trail
- Keywords:
Haploinsufficiency;
Genes;
Mutation
- From:
Chinese Journal of Pediatrics
2020;58(3):218-222
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To explore the clinical phenotype, immunological features, pathogenesis and gene variation of a case with A20 haploinsufficiency (HA20).
Methods:A patient diagnosed with tumor necrosis factor α-induced protein 3 (TNFAIP3) mutated HA20 was admitted into Shenzhen Children′s Hospital in May,2019.The clinical data was analyzed. Flow cytometry was used to detect the patient′s peripheral blood lymphocyte subsets, and also, the percentage of follicular helper T cell (TFH) cells in the patient and thirteen healthy controls. After the construction of empty vector, wild-type and mutant plasmid vectors, a wild-type or mutant overexpression system of the TNFAIP3 gene was established in 293T cells and Hela cells. Then, the expression level of A20 in 293T cells and the expression of inhibitor K binding α (IKBα) in green fluorescent protein (GFP)+Hela cells before and after tumor necrosis factor α (TNF-α) stimulation were measured, to verify the pathogenicity of this variation.
Results:A 5 years and 11 months old boy, presented with recurrent oral ulcer, abdominal pain, joint swelling and arthralgia. Oral ulcer, chronic skin rashes, knee joint swelling were observed. The levels of inflammatory markers were increased. Colonoscopy showed congestion of mucosa and multiple ulcers in terminal ileum and ileocecus. The absolute number of naive B cells was 124×106 cells/L (reference range 147×106-431×106 cells/L), accounting for 0.430 of the total B cells (reference range 0.484-0.758). Compared to healthy controls (0.016-0.071), the percentage of TFH cells in CD4+T cells was much lower (0.008).A heterozygous mutation of TNFAIP3 gene (c.909_913 del, p.L303fs) was identified by genetic analysis. In vitro study showed that truncated A20 protein was expressed in TNFAIP3 mutant overexpressed 293T cells, which verified the pathogenicity of this variation. Besides, after TNF-α stimulation, the degradation rate of IkBα protein in mutant overexpressed Hela cells (35%) was between the other two groups (15% in the wild-type group and 57% in the non-loaded group).
Conclusions:This case with HA20 due to a de novo TNFAIP3 gene mutation presents with early onset Behcet-like autoinflammatory syndrome. This variation leads to expression of truncated A20 protein, enhanced degradation of IkBα, and further activation of nuclear factor κB signaling pathway.
