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01-11-2019 | Systemic Lupus Erythematosus | Original Article

A De Novo Frameshift Mutation in TNFAIP3 Impairs A20 Deubiquitination Function to Cause Neuropsychiatric Systemic Lupus Erythematosus

Authors: Ruonan Duan, Qi Liu, Jiangxia Li, Xianli Bian, Qianqian Yuan, Yan Li, Feng Long, Shang Gao, Shijun Wei, Pengyu Li, Fei Gao, Wenjie Sun, Xi Li, Qiji Liu

Published in: Journal of Clinical Immunology | Issue 8/2019

Abstract

Purpose

Genome-wide association study of systemic lupus erythematosus (SLE) revealed tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) as a susceptibility gene. Here, we report a de novo mutation in TNFAIP3 in a Chinese patient with neuropsychiatric SLE (NPSLE).

Methods

Whole exome sequencing was performed for the patient and healthy members from the family. Suspected pathogenic variants were further analyzed and co-segregation was confirmed by Sanger sequencing. Real-time PCR and western blot were performed with peripheral blood mononuclear cells (PBMCs) and patient-derived T cells. Transfected HEK293T cells, human umbilical vein endothelial cells, normal human astrocytes, and microglia were used for in vitro studies.

Results

A de novo frameshift mutation in TNFAIP3 was found in the NPSLE patient. Western blot analysis showed activated NF-κB and mitogen-activated protein kinase pathways. Real-time PCR revealed elevated expression of pro-inflammatory cytokines. On immunoprecipitation assay, the mutant A20 altered the K63-linked ubiquitin level of TRAF6 via its ubiquitin-editing function.

Conclusions

The mutant A20 may play a role in weakening the tight junction of the blood-brain barrier to cause neurologic symptoms. We report a rare variant of TNFAIP3 in a patient with NPSLE and reveal its autoimmune disease–causing mechanism in both peripheral tissues and the central nervous system.

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Title: A De Novo Frameshift Mutation in TNFAIP3 Impairs A20 Deubiquitination Function to Cause Neuropsychiatric Systemic Lupus Erythematosus
Authors: Ruonan Duan
Qi Liu
Jiangxia Li
Xianli Bian
Qianqian Yuan
Yan Li
Feng Long
Shang Gao
Shijun Wei
Pengyu Li
Fei Gao
Wenjie Sun
Xi Li
Qiji Liu
Publication date: 01-11-2019
Publisher: Springer US
Keywords: Systemic Lupus Erythematosus
Cytokines
Published in: Journal of Clinical Immunology / Issue 8/2019
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-019-00695-4

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A De Novo Frameshift Mutation in TNFAIP3 Impairs A20 Deubiquitination Function to Cause Neuropsychiatric Systemic Lupus Erythematosus

Abstract

Purpose

Methods

Results

Conclusions

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Abstract

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