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, Ogata, Shohei, Ueno, Hiroo, Yoshida, Kenichi, Yeh, Tzuwen, Hoshino, Akihiro, Piao, Jinhua, Yamashita, Motoy, Nanya, Mai, Okano, Tsubasa, Kajiwara, Michiko, Kanegane, Hirokazu, Muramatsu, Hideki, Okuno, Yusuke, Shiraishi, Yuichi, Chiba, Kenichi, Tanaka, Hiroko, Bando, Yuki, Kato, Motohiro, Hayashi, Yasuhide, Miyano, Satoru, Imai, Kohsuke, Ogawa, Seishi, Kojima, Seiji, Morio, Tomohiro
• 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; Genomes; Germ-Line Mutation; Haploinsufficiency; Humans; Immunoglobulins; Infant; Kinases; Leukocytes, Mononuclear - immunology; Lymphocytes; Male; Mutation; NF-kappa B - immunology; Patients; Pediatrics; Phenotype; Proteins; Science; Signal transduction; TNFAIP3 (A20); Transcription; Tumor Necrosis Factor alpha-Induced Protein 3 - genetics; Tumor Necrosis Factor alpha-Induced Protein 3 - immunology; CASP; WES; IKK; DNT; MAPK; TNFAIP3 (A20); ALPS; GFP; NF-κB; Autoimmune lymphoproliferative syndrome; TRAF6; NEMO; WT; TNF receptor–associated factor 6; Whole-exome sequencing; Caspase; Mitogen-activated protein kinase; Wild-type; IκB kinase; NF-κB essential modulator; Double-negative T; Green fluorescent protein; Nuclear factor κB
• DOI: 10.1016/j.jaci.2016.09.038
• ISSN: 0091-6749; 1097-6825

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. The aim of the present study was to elucidate the genetic cause of the ALPS-like phenotype. Candidate genes associated with the ALPS-like phenotype were screened by using whole-exome sequencing. The functional effect of the identified mutations was examined by analyzing the activity of related signaling pathways. A de novo heterozygous frameshift mutation of TNF-α–induced protein 3 (TNFAIP3, A20), a negative regulator of the nuclear factor κB pathway, was identified in one of the patients exhibiting the ALPS-like phenotype. Increased activity of the nuclear factor κB pathway was associated with haploinsufficiency of TNFAIP3 (A20). Haploinsufficiency of TNFAIP3 (A20) by a germline heterozygous mutation leads to the ALPS phenotype.