Alterations in nuclear factor kappa B (NF‐κB) essential modulator (NEMO; HUGO‐approved symbol IKBKG) underlie most cases of ectodermal dysplasia with immune deficiency (EDI), a human disorder characterized by anhidrosis with diminished immunity. EDI has also been associated with a single heterozygous mutation at position Ser32 of the NF‐κB inhibitor IκBα, one of two phosphorylation sites that are essential for targeting IκBα for proteasomal degradation and hence for activation of NF‐κB. We report a novel heterozygous nonsense mutation in the IKBA (HUGO‐approved symbol, NFKBIA) gene of a 1‐year‐old male child with EDI that introduces a premature termination codon at position Glu14. An in‐frame methionine downstream of the nonsense mutation allows for reinitiation of translation. The resulting N‐terminally truncated protein lacks both serine phosphorylation sites and inhibits NF‐κB signaling by functioning as a dominant negative on NF‐κB activity in lymphocytes and monocytes. These findings support the scanning model for translation initiation in eukaryotes and confirm the critical role of the NF‐κB in the human immune response. Hum Mutat 29(6), 861–868, 2008. Published 2008, Wiley‐Liss, Inc.