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

Authors
  • Duan, Ruonan1, 2
  • Liu, Qi2
  • Li, Jiangxia1
  • Bian, Xianli1
  • Yuan, Qianqian1
  • Li, Yan1
  • Long, Feng1
  • Gao, Shang1
  • Wei, Shijun1
  • Li, Pengyu1
  • Gao, Fei1
  • Sun, Wenjie1
  • Li, Xi1
  • Liu, Qiji1
  • 1 Shandong University School of Basic Medical Sciences, No. 44 West Wenhua Road, Jinan, Shandong, 250012, China , Jinan (China)
  • 2 Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China , Jinan (China)
Type
Published Article
Journal
Journal of Clinical Immunology
Publisher
Springer-Verlag
Publication Date
Oct 17, 2019
Volume
39
Issue
8
Pages
795–804
Identifiers
DOI: 10.1007/s10875-019-00695-4
Source
Springer Nature
Keywords
License
Yellow

Abstract

PurposeGenome-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).MethodsWhole 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.ResultsA 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.ConclusionsThe 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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