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

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.