Novel nonsense gain-of-function NFKB2 mutations associated with a combined immunodeficiency phenotype

Hye Sun Kuehn, Julie E. Niemela, Karthik Sreedhara, Jennifer L. Stoddard, Jennifer Grossman, Christian A. Wysocki, M. Teresa de la Morena, Mary Garofalo, Jingga Inlora, Michael P. Snyder, David B. Lewis, Constantine A. Startakis, Thomas A. Fleisher and Sergio D. Rosenzweig

Key points

  • Opposite to previously described <italic>NFKB2</italic> DN changes, <italic>NFKB2</italic> GOF mutations are associated with CID without endocrine or ectodermal manifestations.

  • As most autosomal dominant primary immunodeficiencies, <italic>NFKB2</italic> GOF changes have incomplete penetrance and variable expressivity.


NF-κB signaling through its NFKB1-dependant canonical and NFKB2-dependant non-canonical pathways play distinctive roles in a diverse range of immune processes. Recently, mutations in these two genes have been associated with common variable immunodeficiency (CVID). While studying patients with genetically-uncharacterized primary immunodeficiencies we detected two novel nonsense gain-of-function (GOF) NFKB2 mutations in three patients from two families (E418X and R635X), and a novel missense change in another patient (S866R). Their immunophenotype was assessed by flow-cytometry and protein expression; activation of canonical and non-canonical pathways was examined in PBMCs and transfected HEK293T cells through immunoblotting, immunohistochemistry, luciferase activity, real time PCR, and multiplex assays. The S866R change disrupted a C-terminus NF-κB2 critical site affecting protein phosphorylation and nuclear translocation, resulting in CVID with ACTH deficiency, GH deficiency, and mild ectodermal dysplasia as previously described. In contrast, the nonsense mutations E418X and R635X observed in three patients led to constitutive nuclear localization and activation of both canonical and non-canonical NF-κ pathways, resulting in a combined immunodeficiency (CID) without endocrine or ectodermal manifestations. These changes were also found in two asymptomatic relatives. Thus, these novel NFKB2 GOF mutations produce a non-fully penetrant CID phenotype through a different pathophysiologic mechanism than previously described for mutations in NFKB2.

  • Submitted May 1, 2017.
  • Accepted July 9, 2017.