Female mice heterozygous for IKKγ/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti
Female mice heterozygous for IKKγ/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti
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DOI：
10.1016/s1097-2765(00)80262-2
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发表时间：
2000-06-01
期刊：
影响因子：
16
通讯作者：
Karin, M
中科院分区：
文献类型：
--
作者：
Makris, C;Godfrey, VL;Karin, M
IKK γ/NEMO是I κ B激酶（IKK）的基本调节亚基，由小鼠和人类的X连锁基因编码。它是NF-κ B活化和抵抗TNF诱导的细胞凋亡所必需的。Ikk γ/Nemo缺陷杂合子雌性小鼠发生独特的皮肤病，其特征在于角质形成细胞过度增殖、皮肤炎症、角化过度和细胞凋亡增加。虽然Ikk γ（+/-）雌性最终恢复，但Ikk γ（-）雄性在子宫内死亡。这些症状和遗传模式与色素失禁症（IP）非常相似，IP是一种人类遗传性皮肤病，具有IKK γ/NEMO基因座。事实上，IP患者的活检组织和细胞表现出IKK γ/NEMO表达缺陷，但IKK催化亚基表达正常。这种独特的自限性疾病是第一种与IKK信号通路遗传相关的疾病，依赖于X染色体失活。我们认为IKK γ/NEMO缺陷细胞引发炎症反应，最终导致其死亡。
IKK gamma/NEMO is the essential regulatory subunit of the I kappa B kinase (IKK), encoded by an X-linked gene in mice and humans. It is required for NF-kappa B activation and resistance to TNF-induced apoptosis. Female mice heterozygous for Ikk gamma/Nemo deficiency develop a unique dermatopathy characterized by keratinocyte hyperproliferation, skin inflammation, hyperkeratosis, and increased apoptosis. Although Ikk gamma(+/-) females eventually recover, Ikk gamma(-) males die in utero. These symptoms and inheritance pattern are very similar to those of incontinentia pigmenti (IP), a human genodermatosis, synthenic with the IKK gamma/NEMO locus. Indeed, biopsies and cells from IP patients exhibit defective IKK gamma/NEMO expression but normal expression of IKK catalytic subunits. This unique self-limiting disease, the first to be genetically linked to the IKK signaling pathway, is dependent on X-chromosome inactivation. We propose that the IKK gamma/NEMO-deficient cells trigger an inflammatory reaction that eventually leads to their death.