| First Author | Cardinez C | Year | 2018 |
| Journal | J Exp Med | Volume | 215 |
| Issue | 11 | Pages | 2715-2724 |
| PubMed ID | 30337470 | Mgi Jnum | J:290616 |
| Mgi Id | MGI:6273002 | Doi | 10.1084/jem.20180639 |
| Citation | Cardinez C, et al. (2018) Gain-of-function IKBKB mutation causes human combined immune deficiency. J Exp Med 215(11):2715-2724 |
| abstractText | 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-kappaB signaling. IKK2(V203I) results in enhanced NF-kappaB 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. |
