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

被引：62

作者：

Cardinez, Chelisa ^{[1
,2
,3
]}

Miraghazadeh, Bahar ^{[1
,2
,3
]}

Tanita, Kay ^{[4
]}

da Silva, Elizabeth ^{[2
]}

Hoshino, Akihiro ^{[4
]}

Okada, Satoshi ^{[5
]}

Chand, Rochna ^{[1
,2
,3
]}

Asano, Takaki ^{[5
]}

Tsumura, Miyuki ^{[5
]}

Yoshida, Kenichi ^{[6
]}

Ohnishi, Hidenori ^{[7
]}

Kato, Zenichiro ^{[7
,8
]}

Yamazaki, Masahide ^{[9
]}

Okuno, Yusuke ^{[10
]}

Miyano, Satoru ^{[11
,12
]}

Kojima, Seiji ^{[13
]}

Ogawa, Seishi ^{[6
]}

Andrews, T. Daniel ^{[1
,3
]}

Field, Matthew A. ^{[1
,3
,14
]}

Burgio, Gaetan ^{[3
]}

Morio, Tomohiro ^{[4
]}

Vinuesa, Carola G. ^{[1
,3
]}

Kanegane, Hirokazu ^{[4
]}

Cook, Matthew C. ^{[1
,2
,3
]}

机构：

[1] Australian Natl Univ, Ctr Personalised Immunol, Canberra, ACT, Australia

[2] Canberra Hosp, Dept Immunol, Canberra, ACT, Australia

[3] Australian Natl Univ, John Curtin Sch Med Res, Dept Immunol & Infect Dis, Canberra, ACT, Australia

[4] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Child Hlth & Dev, Tokyo, Japan

[5] Hiroshima Univ, Grad Sch Biomed & Hlth Sci, Dept Pediat, Hiroshima, Japan

[6] Kyoto Univ, Grad Sch Med, Dept Pathol & Tumor Biol, Kyoto, Japan

[7] Gifu Univ, Grad Sch Med, Dept Pediat, Gifu, Japan

[8] Gifu Univ, United Grad Sch Drug Discovery & Med Informat Sci, Struct Med, Gifu, Japan

[9] Keiju Med Ctr, Dept Internal Med, Nanao, Japan

[10] Nagoya Univ Hosp, Ctr Adv Med & Clin Res, Nagoya, Aichi, Japan

[11] Univ Tokyo, Human Genome Ctr, Inst Med Sci, Lab DNA Informat Anal, Tokyo, Japan

[12] Univ Tokyo, Human Genome Ctr, Inst Med Sci, Lab Sequence Anal, Tokyo, Japan

[13] Nagoya Univ, Dept Pediat, Grad Sch Med, Nagoya, Aichi, Japan

[14] James Cook Univ, Australian Inst Trop Hlth & Med, Cairns, Australia

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2018年 / 215卷 / 11期

基金：

英国医学研究理事会; 日本学术振兴会;

关键词：

NF-KAPPA-B; INBORN-ERRORS; COMBINED IMMUNODEFICIENCY; TRANSCRIPTION FACTOR; P50; SUBUNIT; EXPRESSION; GENERATION; PATHWAY; INNATE; CARD11;

D O I：

10.1084/jem.20180639

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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-kappa B signaling. IKK2(V203I) results in enhanced NF-kappa B 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.

引用

页码：2715 / 2724

页数：10

共 36 条

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