A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency
✍ Scribed by Eduardo Lopez-Granados; Jeffrey E. Keenan; Matthew C. Kinney; Harvey Leo; Neal Jain; Chi A. Ma; Ralph Quinones; Erwin W. Gelfand; Ashish Jain
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 290 KB
- Volume
- 29
- Category
- Article
- ISSN
- 1059-7794
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✦ Synopsis
Communicated by Mauno Vihinen
Alterations in nuclear factor kappa B (NF-jB) 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-jB inhibitor IjBa, one of two phosphorylation sites that are essential for targeting IjBa for proteasomal degradation and hence for activation of NF-jB. 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-jB signaling by functioning as a dominant negative on NF-jB activity in lymphocytes and monocytes. These findings support the scanning model for translation initiation in eukaryotes and confirm the critical role of the NF-jB in the human immune response. Hum Mutat 29(6),