Atypical forms of incontinentia pigmenti in male individuals result from mutations of a cytosine tract in exon 10 of NEMO (IKK-γ)
Atypical forms of incontinentia pigmenti in male individuals result from mutations of a cytosine tract in exon 10 of NEMO (IKK-γ)
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DOI：
10.1086/318806
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发表时间：
2001-03-01
影响因子：
9.8
通讯作者：
Nelson, DL
中科院分区：
文献类型：
--
作者：
Aradhya, S;Courtois, G;Nelson, DL
家族性色素失禁（IP [MIM 308310]）或Bloch-Sulzberger综合征是一种X连锁显性和男性致死性疾病。我们最近证明，NEMO（IKK-γ）突变，编码NF-κ B信号通路的关键组成部分，是IP的原因。几乎所有的突变消除NEMO的生产，导致典型的倾斜的X失活在女性个体和男性个体的致死性，可能通过增强敏感性细胞凋亡。大多数突变也引起IP的经典体征，但在这份报告中，我们描述了两个突变的非典型表型的家庭。值得注意的是，每个家庭都有一个男性个体出现异常体征，包括出生后存活和免疫功能障碍或造血功能障碍。我们在这些家族中发现了两个重复突变，位于NEMO外显子10的胞嘧啶区，这两个突变都去除了蛋白质C端的锌指。在其他家族的同一基因组中也发现了两个缺失突变。然而，只有重复突变允许男性个体存活，而受影响的女性个体的重复突变表现出随机或轻微的X失活偏斜。类似地，在存在重复突变的情况下，NF-κ B活化减少，并且在具有缺失突变的细胞中完全不存在。这些结果强烈表明，男性个体也可能患有NEMO突变引起的IP，因此我们敦促重新评估诊断标准。
Familial incontinentia pigmenti (IP [MIM 308310]), or Bloch-Sulzberger syndrome, is an X-linked dominant and male-lethal disorder. We recently demonstrated that mutations in NEMO (IKK-gamma), which encodes a critical component of the NF-kappaB signaling pathway, were responsible for IP. Virtually all mutations eliminate the production of NEMO, causing the typical skewing of X inactivation in female individuals and lethality in male individuals, possibly through enhanced sensitivity to apoptosis. Most mutations also give rise to classic signs of IP, but, in this report, we describe two mutations in families with atypical phenotypes. Remarkably, each family included a male individual with unusual signs, including postnatal survival and either immune dysfunction or hematopoietic disturbance. We found two duplication mutations in these families, at a cytosine tract in exon 10 of NEMO, both of which remove the zinc (Zn) finger at the C-terminus of the protein. Two deletion mutations were also identified in the same tract in additional families. However, only the duplication mutations allowed male individuals to survive, and affected female individuals with duplication mutations demonstrated random or slight skewing of X inactivation. Similarly, NF-kappaB activation was diminished in the presence of duplication mutations and was completely absent in cells with deletion mutations. These results strongly indicate that male individuals can also suffer from IP caused by NEMO mutations, and we therefore urge a reevaluation of the diagnostic criteria.