Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome

• Published in: Journal of allergy and clinical immunology Vol. 139; no. 6; pp. 1914 - 1922
• Main Authors: Takagi, Masatoshi, M.D., Ph.D, Ogata, Shohei, M.D., Ph.D, Ueno, Hiroo, M.D, Yoshida, Kenichi, M.D., Ph.D, Yeh, Tzuwen, B.Sc, Hoshino, Akihiro, M.D., Ph.D, Piao, Jinhua, D.D.S., Ph. D, Yamashita, Motoy, M.D, Nanya, Mai, Ph. D, Okano, Tsubasa, M.D, Kajiwara, Michiko, M.D., Ph.D, Kanegane, Hirokazu, M.D., Ph.D, Muramatsu, Hideki, M.D., Ph.D, Okuno, Yusuke, M.D., Ph.D, Shiraishi, Yuichi, M.D., Ph.D, Chiba, Kenichi, B.A, Tanaka, Hiroko, B.S, Bando, Yuki, M.D., Ph.D, Kato, Motohiro, M.D., Ph.D, Hayashi, Yasuhide, M.D., Ph.D, Miyano, Satoru, Ph.D, Imai, Kohsuke, M.D., Ph.D, Ogawa, Seishi, M.D., Ph.D, Kojima, Seiji, M.D., Ph.D, Morio, Tomohiro, M.D., Ph.D
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2017; Elsevier Limited
• Subjects: Allergy and Immunology; Apoptosis; Autoimmune diseases; Autoimmune lymphoproliferative syndrome; Autoimmune Lymphoproliferative Syndrome - genetics; Autoimmune Lymphoproliferative Syndrome - immunology; Cells, Cultured; Children; Disease; Fas antigen; Frameshift mutation; Functional anatomy; Genes; Genomes; Germ-Line Mutation; Haploinsufficiency; Humans; Immunoglobulins; Infant; Kinases; Leukocytes, Mononuclear - immunology; Lymphocytes; Male; Mutation; NF-kappa B - immunology; Patients; Pediatrics; Phenotype; Proteins; Revisions; Science; Signal transduction; TNFAIP3 (A20); Transcription; Tumor Necrosis Factor alpha-Induced Protein 3 - genetics; Tumor Necrosis Factor alpha-Induced Protein 3 - immunology; carboxyfluorescein diacetate succinimidyl ester; double-negative T; DNT; PBMC; TNFAIP3 (A20); ALPS; CSFE; single nucleotide variant; autoimmune lymphoproliferative syndrome; peripheral blood-derived mononuclear cell; enzyme-linked immunosorbent assay; SNV; ELISA; CASP; WES; IKK; MAPK; GFP; NF-κB; Autoimmune lymphoproliferative syndrome; TRAF6; NEMO; WT
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2016.09.038

Abstract Background Autoimmune diseases in children are rare and can be difficult to diagnose. Autoimmune lymphoproliferative syndrome (ALPS) is a well-characterized pediatric autoimmune disease caused by mutations in genes associated with the FAS-dependent apoptosis pathway. In addition, various genetic alterations are associated with the ALPS-like phenotype. Objective The aim of the present study was to elucidate the genetic etiology of the ALPS-like phenotype. Methods Candidate genes associated with the ALPS-like phenotype were screened by whole exome sequencing. The functional impact of the identified mutations was examined by analyzing the activity of related signaling pathways. Results A de novo heterozygous frameshift mutation of tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20), a negative regulator of the NF-κB pathway, was identified in one of patients who exhibiting ALPS-like phenotype. Increased activity of the NF-κB pathway was associated with haploinsufficiency of TNFAIP3 (A20). Conclusion Haploinsufficiency of TNFAIP3 (A20) by a germline heterozygous mutation leads to the ALPS phenotype.