Mutations disrupting the kinase domain of IKKα lead to immunodeficiency and immune dysregulation in humans. Mutations disrupting the kinase domain of IKKα lead to immunodeficiency and immune dysregulation in humans

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. Overall design: SV40-fibroblasts were stimulated with human TNFalpha 10 ng/mL or Poly I:C 10 ug/mL for 6h or left unstimulated and RNA were harvested with a DNAse digestion step. RNA sequencing was performed on total RNA extracts.