Centre for Personalised Immunology, Australian National University, Canberra, Australia.
Department of Immunology Canberra Hospital, Canberra, Australia.
J Exp Med. 2018 Nov 5;215(11):2715-2724. doi: 10.1084/jem.20180639. Epub 2018 Oct 18.
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 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. encodes IKK2, which activates NF-κB signaling. IKK2 results in enhanced NF-κB signaling, as well as T and B cell functional defects. IKK2 is a highly conserved residue, and to prove causation, we generated an accurate mouse model by introducing the precise orthologous codon change in 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.
遗传突变导致许多严重的早期免疫缺陷。相比之下，不太严重和发病较晚的免疫性疾病，包括无家族病史的患者，仍然知之甚少。对两组此类患者进行全外显子组测序，在两个不同家系中发现了一种新的杂合性新生错义突变（c.607G>A），先证者表现为免疫失调、联合 T 和 B 细胞缺陷、炎症和上皮缺陷。 编码 IKK2，它激活 NF-κB 信号。IKK2 导致 NF-κB 信号增强，以及 T 和 B 细胞功能缺陷。IKK2 是一个高度保守的残基，为了证明因果关系，我们使用 CRISPR/Cas9 在 中引入了精确的同源密码子变化，从而产生了一个精确的小鼠模型。携带这种错义突变的小鼠和人类表现出非常相似的细胞和生化表型。由 CRISPR/Cas9 工程改造的精确小鼠模型可以帮助我们描述由新生种系突变引起的新型综合征，并深入了解发病机制。
