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

Publication date: Available online 12 November 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Masatoshi Takagi, Shohei Ogata, Hiroo Ueno, Kenichi Yoshida, Tzuwen Yeh, Akihiro Hoshino, Jinhua Piao, Motoy Yamashita, Mai Nanya, Tsubasa Okano, Michiko Kajiwara, Hirokazu Kanegane, Hideki Muramatsu, Yusuke Okuno, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Yuki Bando, Motohiro Kato, Yasuhide Hayashi, Satoru Miyano, Kohsuke Imai, Seishi Ogawa, Seiji Kojima, Tomohiro Morio
BackgroundAutoimmune 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.ObjectiveThe aim of the present study was to elucidate the genetic etiology of the ALPS-like phenotype.MethodsCandidate 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.ResultsA 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).ConclusionHaploinsufficiency of TNFAIP3 (A20) by a germline heterozygous mutation leads to the ALPS phenotype.

Teaser

Haploinsufficiency of TNFAIP3 (A20) by frameshift germline mutation causes autoimmune lymphoproliferative syndrome.


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