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

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).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.A de novo frameshift mutation in TNFAIP3 was found in the NPSLE patient. Western blot analysis showed activated NF-?B 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.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.
Mesh Terms:
Adult, Blood-Brain Barrier, Cytokines, DNA Mutational Analysis, Female, Frameshift Mutation, HEK293 Cells, Human Umbilical Vein Endothelial Cells, Humans, Lupus Vasculitis, Central Nervous System, Microglia, Recombinant Proteins, Tumor Necrosis Factor alpha-Induced Protein 3, Ubiquitination, Whole Exome Sequencing
J. Clin. Immunol.
Date: Dec. 01, 2018
Download Curated Data For This Publication
222884
Switch View:
  • Interactions 1