Gain-of-function IKBKB mutation causes human combined immune deficiency

Cardinez, Chelisa, Miraghzadeh, Bahar, Tanita, Kay, da Silva, Elizabeth, Hoshino, Akihiro, Okada, Satoshi, Chand, Rochna, Asano, Takaki, Tsumura, Miyuki, Yoshida, Kenichi, Ohnish, Hidenori, Kato, Zenichiro, Yamazki, Masahide, Okuno, Yusuke, Miyano, Satoru, Kojima, Seiji, Ogawa, Seishi, Andrews, T. Daniel, Field, Matthew A., Burgio, Gaetan, Morio, Tomohiro, Vinuesa, Carola G., Kanegane, Hirokazu, and Cook, Matthew C. (2018) Gain-of-function IKBKB mutation causes human combined immune deficiency. The Journal of Experimental Medicine, 215 (11). pp. 2715-2724.

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Abstract

Genetic mutations account for many devastating early onset immune deficiencies. In contrast, less severe and later onset immune diseases, including in patients with no prior family history, remain poorly understood. Whole exome sequencing in two cohorts of such patients identified a novel heterozygous de novo IKBKB missense mutation (c.607G>A) in two separate kindreds in whom probands presented with immune dysregulation, combined T and B cell deficiency, inflammation, and epithelial defects. IKBKB encodes IKK2, which activates NF-κB signaling. IKK2V203I results in enhanced NF-κB signaling, as well as T and B cell functional defects. IKK2V203 is a highly conserved residue, and to prove causation, we generated an accurate mouse model by introducing the precise orthologous codon change in Ikbkb using CRISPR/Cas9. Mice and humans carrying this missense mutation exhibit remarkably similar cellular and biochemical phenotypes. Accurate mouse models engineered by CRISPR/Cas9 can help characterize novel syndromes arising from de novo germline mutations and yield insight into pathogenesis.

Item ID: 56052
Item Type: Article (Research - C1)
ISSN: 1540-9538
Copyright Information: Copyright © 2018 Crown copyright. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
Funders: National Health and Medical Research Council (NHMRC), Bev and Alan Harvey Bequest (BAHB), Japan Society for the Promotion of Science (JSPS), Japan Agency for Medical Research and Development (JAMRD)
Projects and Grants: NHMRC 107464, NHMRC 1079648, NHMRC 1113577, JSPS KAKENHI JP16H05355, JSPS 16K15528, JSPS JP26461570, JSPS JP17K10099, JAMRD Practical Research Project for Rare/Intractable Diseases
Date Deposited: 13 Dec 2018 03:48
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320406 Immunogenetics (incl. genetic immunology) @ 50%
31 BIOLOGICAL SCIENCES > 3102 Bioinformatics and computational biology > 310204 Genomics and transcriptomics @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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