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

J Exp Med. 2018 Nov 5;215(11):2715-2724. doi: 10.1084/jem.20180639.

Chelisa Cardinez ¹ ² ³, Bahar Miraghazadeh ¹ ² ³, Kay Tanita ⁴, Elizabeth da Silva ², Akihiro Hoshino ⁴, Satoshi Okada ⁵, Rochna Chand ¹ ² ³, Takaki Asano ⁵, Miyuki Tsumura ⁵, Kenichi Yoshida ⁶, Hidenori Ohnishi ⁷, Zenichiro Kato ⁷ ⁸, Masahide Yamazaki ⁹, Yusuke Okuno ¹⁰, Satoru Miyano ¹¹ ¹², Seiji Kojima ¹³, Seishi Ogawa ⁶, T Daniel Andrews ¹ ³, Matthew A Field ¹ ³ ¹⁴, Gaetan Burgio ³, Tomohiro Morio ⁴, Carola G Vinuesa ¹ ³, Hirokazu Kanegane ¹⁵, Matthew C Cook ¹⁶ ² ³

Affiliations

1 Centre for Personalised Immunology, Australian National University, Canberra, Australia.
2 Department of Immunology Canberra Hospital, Canberra, Australia.
3 Department of Immunology and Infectious Diseases, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
4 Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
5 Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
6 Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
7 Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan.
8 Structural Medicine, United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan.
9 Department of Internal Medicine, Keiju Medical Center, Nanao, Japan.
10 Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
11 Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
12 Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
13 Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
14 Australian Institute for Tropical Health and Medicine, James Cook University, Cairns, Australia.
15 Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan [email protected].
16 Centre for Personalised Immunology, Australian National University, Canberra, Australia [email protected].

PMID: 30337470 DOI: 10.1084/jem.20180639

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. IKK2^V203I results in enhanced NF-κB signaling, as well as T and B cell functional defects. IKK2^V203 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.

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