A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency
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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DOI：
10.1002/humu.20740
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发表时间：
2008-06-01
期刊：
影响因子：
3.9
通讯作者：
Jain, Ashish
中科院分区：
文献类型：
--
作者：
Granados, Eduardo Lopez;Keenan, Jeffrey E.;Jain, Ashish
核因子-kappa B(NF-kappa B)必需调节剂(NEMO；雨果批准的代号IKBKG)的改变是大多数外胚层发育不良伴免疫缺陷(EDI)的基础，EDI是一种以多汗症和免疫力降低为特征的人类疾病。EDI还与核因子-kappa B抑制剂I kappa BαSer32位的单个杂合性突变有关，这是针对I kappa Bα蛋白酶体降解从而激活核因子-kappa B的两个磷酸化位点之一。我们报告了一种新的杂合性无义突变，该突变发生在1岁患有EDI的男性儿童中，在Glu14位引入了一个提前终止密码子。无义突变下游的框内蛋氨酸允许重新启动翻译。由此产生的N末端截短的蛋白既缺少丝氨酸磷酸化位点，又通过在淋巴细胞和单核细胞中作为核因子-kappa B活性的显性负向来抑制核因子-kappa B信号转导。这些发现支持真核生物翻译起始的扫描模型，并证实了核因子-kappa B在人类免疫反应中的关键作用。
Alterations in nuclear factor kappa B (NF-kappa 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-kappa B inhibitor I kappa B alpha, one of two phosphorylation sites that are essential for targeting I kappa B alpha for proteasomal degradation and hence for activation of NF-kappa B. We report a novel heterozygous nonsense mutation in the IKBA (HUGO-approved symbol, NFKBIA) gene of a I 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-kappa B signaling by functioning as a dominant negative on NF-kappa 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-kappa B in the human immune response.