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Case Reports
. 2017 Jun;139(6):1914-1922.
doi: 10.1016/j.jaci.2016.09.038. Epub 2016 Nov 12.

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

Masatoshi Takagi  1 , Shohei Ogata  2 , Hiroo Ueno  3 , Kenichi Yoshida  3 , Tzuwen Yeh  4 , Akihiro Hoshino  4 , Jinhua Piao  4 , Motoy Yamashita  4 , Mai Nanya  4 , Tsubasa Okano  4 , Michiko Kajiwara  5 , Hirokazu Kanegane  4 , Hideki Muramatsu  6 , Yusuke Okuno  6 , Yuichi Shiraishi  7 , Kenichi Chiba  7 , Hiroko Tanaka  8 , Yuki Bando  9 , Motohiro Kato  10 , Yasuhide Hayashi  11 , Satoru Miyano  12 , Kohsuke Imai  4 , Seishi Ogawa  3 , Seiji Kojima  6 , Tomohiro Morio  4
Affiliations
Case Reports

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

Masatoshi Takagi et al. J Allergy Clin Immunol. 2017 Jun.

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 cause of the ALPS-like phenotype.

Methods: 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.

Results: 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).

Conclusion: Haploinsufficiency of TNFAIP3 (A20) by a germline heterozygous mutation leads to the ALPS phenotype.

Keywords: Autoimmune lymphoproliferative syndrome; TNFAIP3 (A20).

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