A De Novo Frameshift Mutation in TNFAIP3 Impairs A20 Deubiquitination Function to Cause Neuropsychiatric Systemic Lupus
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ORIGINAL ARTICLE
A De Novo Frameshift Mutation in TNFAIP3 Impairs A20 Deubiquitination Function to Cause Neuropsychiatric Systemic Lupus Erythematosus Ruonan Duan 1,2 & Qi Liu 3 & Jiangxia Li 1 & Xianli Bian 1 & Qianqian Yuan 1 & Yan Li 1 & Feng Long 1 & Shang Gao 1 & Shijun Wei 1 & Pengyu Li 1 & Fei Gao 1 & Wenjie Sun 1 & Xi Li 1 & Qiji Liu 1 Received: 13 September 2019 / Accepted: 20 September 2019 # Springer Science+Business Media, LLC, part of Springer Nature 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. Keywords K63-linked ubiquitin . neuropsychiatric systemic lupus erythematosus . NF-κB . TNFAIP3 . TRAF6 . blood-brain barrier
Introduction Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disorder that mainly affects women at childbearing age [1]. The nomenclature neuropsychiatric SLE (NPSLE) Ruonan Duan and Qi Liu contributed equally to this work. * Qiji Liu [email protected] 1
Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, Shandong University School of Basic Medical Sciences, No. 44 West Wenhua Road, Jinan 250012, Shandong, China
2
Department of Neurology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
3
Department of Rheumatology, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China
refers to disorders in the central, peripheral, and autonomic nervous systems and syndromes in psychiatry [2]. Such symptoms include headache and mood disturbance in mild conditions as well as myelopathy, stroke, and acute confusion in severe conditions [3]. The prevalence of neuropsychiatric manifestations observed in SLE ranges from 12 to 95%
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