A germline IκBα mutation outside the signal reception domain blocks nuclear translocation of NFκB1 and associates...

IκBα controls the canonical activation of NFκB. IκBα gain-of-function due to NFKBIA variants affecting the N-terminus of IκBα-especially residues 32 and 36-manifests with combined immunodeficiency. The role of NFKBIA variants affecting other IκBα domains has not been described.

Variants in NFKBIA were identified using whole-exome sequencing. IκBα expression has been quantified by flow cytometry and Western blotting. Activation-induced IκBα degradation, NFκB1 activation, and nuclear translocation as well as inflammasome activity were evaluated.

The p.Gln228* variant in NFKBIA, identified in a family with a history of arthritis and psoriasis, did not affect induced degradation of IκBα. Its expression in HEK293T cells confirmed its truncating effect and revealed reduced NFκB activation. Similar to transfected HEK293T cells, peripheral blood mononuclear cells from patients harbouring the p.Gln228* variant displayed substantially reduced nuclear levels of NFκB1 p50. The latter findings suggest that the p.Gln228* variant causes a functional insufficiency of NFκB1. Similar to patients with NFκB1 haploinsufficiency, high serum levels of interleukin (IL)-18, as well as enhanced induced apoptosis-associated speck-like protein containing a caspase recruitment domain speck formation and IL-1β secretion in vitro, suggest enhanced inflammasome activation.

NFKBIA variants not localising to the signal reception domain can affect IκBα function and consequently restrict the canonical activation of NFκB. In contrast to the phenotype of N-terminal variants, which is dominated by combined immunodeficiency, the here-reported C-terminal deletion of IκBα was identified in patients with autoinflammatory arthritis and psoriasis.