A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency.

来自 EBSCO

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作者：

E Lopez-Granados，JE Keenan，MC Kinney，H Leo，N Jain，CA Ma，R Quinones，EW Gelfand，A Jain

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摘要：

Alterations in nuclear factor kappa B (NF-B) 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-B inhibitor IB, one of two phosphorylation sites that are essential for targeting IB for proteasomal degradation and hence for activation of NF-B. 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-B signaling by functioning as a dominant negative on NF-B activity in lymphocytes and monocytes. These findings support the scanning model for translation initiation in eukaryotes and confirm the critical role of the NF-B in the human immune response. Hum Mutat 29(6), 861-868, 2008. Published 2008, Wiley-Liss, Inc.

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关键词：

primary immunodeficiency ectodermal dysplasia EDI lymphocyte activation antigen presenting cell NEMO NF‐κB IKBKG IκBα IKBA