A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency.
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Lopez-Granados E, Keenan JE, Kinney MC, Leo H, Jain N, Ma CA, Quinones R, Gelfand EW, Jain A
A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency.
Hum Mutat. 2008 Jun;29(6):861-8. doi: 10.1002/humu.20740.
- PubMed ID
- 18412279 [ View in PubMed]
- Abstract
Alterations in nuclear factor kappa B (NF-kappaB) 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-kappaB inhibitor IkappaBalpha, one of two phosphorylation sites that are essential for targeting IkappaBalpha for proteasomal degradation and hence for activation of NF-kappaB. 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-kappaB signaling by functioning as a dominant negative on NF-kappaB activity in lymphocytes and monocytes. These findings support the scanning model for translation initiation in eukaryotes and confirm the critical role of the NF-kappaB in the human immune response.