Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Immunology, Medicine, Research & Experimental, Research & Experimental Medicine, NF-KAPPA-B, GERMLINE MUTATIONS, GENE-EXPRESSION, MICE LACKING, T-CELLS, ACTIVATION, PATHWAY, BETA, NF-KAPPA-B2, NFKB2, Humans, I-kappa B Kinase, Female, NF-kappa B, Immunologic Deficiency Syndromes, Mutation, Agammaglobulinemia, Protein Domains, Signal Transduction, HEK293 Cells, G0B5120N#55518763, 1805821N#55901763, C16/18/007#54690355, 11 Medical and Health Sciences, 32 Biomedical and clinical sciences, 42 Health sciences

Abstract:

IKKα, encoded by CHUK, is crucial in the non-canonical NF-κB pathway and part of the IKK complex activating the canonical pathway alongside IKKβ. The absence of IKKα causes fetal encasement syndrome in humans, fatal in utero, while an impaired IKKα-NIK interaction was reported in a single patient and causes combined immunodeficiency. Here, we describe compound heterozygous variants in the kinase domain of IKKα in a female patient with hypogammaglobulinemia, recurrent lung infections, and Hay-Wells syndrome-like features. We showed that both variants were loss-of-function. Non-canonical NF-κB activation was profoundly diminished in stromal and immune cells while the canonical pathway was unexpectedly partially impaired. Reintroducing wt CHUK restored non-canonical NF-κB activation. The patient had neutralizing autoantibodies against type I IFN, akin to non-canonical NF-κB pathway deficiencies. Thus, this is the first case of biallelic CHUK mutations disrupting IKKα kinase function, broadening non-canonical NF-κB defect understanding, and suggesting IKKα's role in canonical NF-κB target gene expression in humans.