Human IκBα Gain of Function: a Severe and Syndromic Immunodeficiency.

Germline heterozygous gain-of-function (GOF) mutations of NFKBIA, encoding IκBα, cause an autosomal dominant (AD) form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). Fourteen unrelated patients have been reported since the identification of the first case in 2003. All mutations enhanced the inhibitory activity of IκBα, by preventing its phosphorylation on serine 32 or 36 and its subsequent degradation. The mutation certainly or probably occurred de novo in 13 patients, whereas it was inherited from a parent with somatic mosaicism in one patient. Eleven mutations, belonging to two groups, were identified: (i) missense mutations affecting S32, S36, or neighboring residues (8 mutations, 11 patients) and (ii) nonsense mutations upstream from S32 associated with the reinitiation of translation downstream from S36 (3 mutations, 3 patients). Thirteen patients had developmental features of EDA, the severity and nature of which differed between cases. All patient cells tested displayed impaired NF-κB-mediated responses to the stimulation of various surface receptors involved in cell-intrinsic (fibroblasts), innate (monocytes), and adaptive (B and T cells) immunity, including TLRs, IL-1Rs, TNFRs, TCR, and BCR. All patients had profound B-cell deficiency. Specific immunological features, found in some, but not all patients, included a lack of peripheral lymph nodes, lymphocytosis, dysfunctional α/β T cells, and a lack of circulating γ/δ T cells. The patients had various pyogenic, mycobacterial, fungal, and viral severe infections. Patients with a missense mutation tended to display more severe phenotypes, probably due to higher levels of GOF proteins. In the absence of hematopoietic stem cell transplantation (HSCT), this condition cause death before the age of 1 year (one child). Two survivors have been on prophylaxis (at 9 and 22 years). Six children died after HSCT. Five survived, four of whom have been on prophylaxis (3 to 21 years post HSCT), whereas one has been well with no prophylaxis. Heterozygous GOF mutations in IκBα underlie a severe and syndromic immunodeficiency, the interindividual variability of which might partly be ascribed to the dichotomy of missense and nonsense mutations, and the hematopoietic component of which can be rescued by HSCT.