Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100

Most genetic defects that arrest B-cell development in the bone marrow present early in life with agammaglobulinemia, whereas incomplete antibody deficiency is usually associated with circulating B cells. We report 3 related individuals with a novel form of severe B-cell deficiency associated with partial persistence of serum immunoglobulin arising from a missense mutation in NFKB2. Significantly, this point mutation results in aD865Gsubstitutionandcausesafailureofp100phosphorylationthatblocksprocessing to p52. Severe B-cell deficiency affects mature and transitional cells, mimicking the action of rituximab. This phenotype appears to be dueto disruption of canonical and noncanonical nuclear factor κ B pathways by the mutant p100 molecule. These findings could be informative for therapeutics as well as immunodeficiency.