A novel missense mutation in TNFAIP3 causes haploinsufficiency of A20

A20, encoded by TNFAIP3, is an effective anti-inflammatory molecule that plays a crucial role in inhibiting NF-KB signal transmission and is linked to multiple inflammatory diseases. It has been reported that the haploinsufficiency of A20 (HA20) caused by multiple base mutations in TNFAIP3 shows early-onset spontaneous Behcet-like disease. However, the mechanisms by which A20 mutations involved in inflammatory disease are incompletely defined. Herein, we reported a novel TNFAIP3 (c.1804A > T, p.T602S) variation, which has not been reported before. Summarizing the patient's immunodeficiency phenotype, we aimed to delineate the underlying mechanism for regulation of inflammation and immunity. Candidate genes associated with the Behcetlike phenotypes of the patient were screened and identified by using whole-exome and sanger sequencing. Functional studies were performed in A20(c.1804A > T, p.T602S) patient-derived peripheral blood mononuclear cells (PBMCs) and THP-1 cell lines by lentivirus mediating stable over-expression of A20 and A20(c.1804A > T, p.T602S) to analyze the activity of NF-KB signaling pathway. The clinical manifestations in patients with syndrome are Behcet-like disorder, and sequencing revealed heterozygous mutation in TNFAIP3 (c.1804A > T, p. T602S). Functional tests found that the PBMCs of the patient and his family carrying this heterozygous variant stimulated by LPS, TNF-alpha, or IL-18, increased the levels of inflammatory factors and induced over-activation of the canonical NF-KB signaling pathway. Similar results were also observed in the stable transduction THP-1 (A20, c.1804A>T) cell line stimulated by LPS, TNF-alpha or IL-18. The novel loss-of-function A20 variation (c.1804A > T, p.T602S) causes over-activation of the canonical NF-KB signaling pathway and fail to terminate NF-KB signaling in response to stimulation by inflammatory cytokines. The variation triggers a dominantly-inherited Behcet-like disorder caused by haploinsufficiency of the A20 protein. Identification of the novel A20 mutation attaches great importance to prenatal diagnosis and fetal therapeutic intervention, drastically reducing the risk of newborns suffering from HA20.

Automated summary

A novel TNFAIP3 variation (c.1804A > T, p.T602S) related to Behcet-like disease was reported, causing over-activation of the canonical NF-KB signaling pathway in patient PBMCs. The identified mutation triggers a dominantly inherited Behcet-like disorder due to A20 haploinsufficiency, emphasizing the importance of prenatal diagnosis and therapeutic intervention.