Masatoshi Takagi1, Shohei Ogata2, Hiroo Ueno3, Kenichi Yoshida3, Tzuwen Yeh4, Akihiro Hoshino4, Jinhua Piao4, Motoy Yamashita4, Mai Nanya4, Tsubasa Okano4, Michiko Kajiwara5, Hirokazu Kanegane4, Hideki Muramatsu6, Yusuke Okuno6, Yuichi Shiraishi7, Kenichi Chiba7, Hiroko Tanaka8, Yuki Bando9, Motohiro Kato10, Yasuhide Hayashi11, Satoru Miyano12, Kohsuke Imai4, Seishi Ogawa3, Seiji Kojima6, Tomohiro Morio4. 1. Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: m.takagi.ped@tmd.ac.jp. 2. Department of Pediatrics, Kitasato University, Kanagawa, Japan. 3. Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan. 4. Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan. 5. Department of Transfusion Medicine, Tokyo Medical and Dental University, Tokyo, Japan. 6. Department of Pediatrics, Nagoya University, Nagoya, Japan. 7. Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. 8. Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. 9. Department of Pediatrics, Kitasato University Medical Center, Saitama, Japan. 10. Department of Pediatric Hematology and Oncology Research, National Centre for Child Health and Development, Tokyo, Japan. 11. Gunma Children's Medical Center, Gunma, Japan. 12. Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
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.
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.
Authors: Yajie Li; Erin C Mooney; Sara E Holden; Xia-Juan Xia; David J Cohen; Scott W Walsh; Averil Ma; Sinem E Sahingur Journal: J Immunol Date: 2019-02-13 Impact factor: 5.422