Novel splicing mutation in the NEMO (IKK-gamma) gene with severe immunodeficiency and heterogeneity of X-chromosome inactivation
Novel splicing mutation in the NEMO (IKK-gamma) gene with severe immunodeficiency and heterogeneity of X-chromosome inactivation
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DOI：
10.1002/ajmg.a.31026
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发表时间：
2006-01-01
影响因子：
2
通讯作者：
Steen-Johnsen, J
中科院分区：
文献类型：
--
作者：
Orstavik, KH;Kristiansen, M;Steen-Johnsen, J
我们报道了一个有三个死胎男性的家庭，其中三个受影响的男性小于胎龄并在8个月内死亡，还有一个男性在5岁时死亡。这个男孩长着圆锥形的牙齿，牙齿稀少。他患有严重的细菌感染和炎症性肠病。核因子-kappa B必需调节剂(NEMO)基因突变是导致一组外胚层发育不良和免疫缺陷疾病(EDA-ID)的原因。对NEMO基因的分析显示，第6外显子IVS6+5G->；A(1027+5G->；A)的剪接供体位点的共同序列发生了核苷酸变化，这是以前在EDA-ID中没有描述的。对流产的男性胎儿前成纤维细胞RNA的RT-PCR分析表明，外显子4、5和6跳过，导致NEMO抗体显示出约35 kDa的截短蛋白。外显子4、5和6的跳过不影响由外显子7、8、9和10编码的Nemo的C-末端的ORF，该外显子包含Nemo的卷曲基序(CC2)、亮氨酸拉链(LZ)和锌指基序(ZF)亚域。I-kappa Bα在胎儿成纤维细胞中的降解明显受损，提示NF-kappa B信号转导受损。一个健康携带者的X-in激活模式完全扭曲，而正常的X-in激活，而另外两个携带者的X-in失活模式是随机的。该家系可能代表了EDA-ID疾病中的一种新表型。从X失活表型的异质性，我们得出结论，这种突变不足以对外周血细胞致命。(C)2005年Wiley-Liss，Inc.
We report on a family with three stillborn males, three affected males who were small for gestational age and died within 8 months, and one male who died at age 5 years. This boy had cone-shaped teeth and oligoodontia. He had serious bacterial infections and inflammatory bowel disease. Mutations in the NF-kappa B essential modulator (NEMO) gene have recently been shown to be the cause of a group Of ectodermal dysplasia and immunodeficiency disorders (EDA-ID). Analysis of the NEMO gene revealed a nucleotide change in the consensus sequence of the splicing donor site of exon 6 IVS6 + 5G -> A(1027 + 5G -> A), which has not previously been described in EDA-ID. RT-PCR analysis of fibroblast RNA front an aborted affected male fetus demonstrated a skipping of exons 4, 5, and 6 which resulted in a truncated protein of about 35 kDa revealed by NEMO antibody. The skipping of exons 4, 5, and 6 did not affect the ORF of the C-terminal of NEMO encoded by exons 7, 8, 9, and 10, which contains a coiled-coil motif (CC2), a leucin-zipper (LZ), and a zinc finger motif (ZF) sub-domains of NEMO. I kappa B alpha degradation was strongly impaired in the fetal fibroblasts, suggesting an impaired NF-kappa B signaling. One healthy carrier had a completely skewed X-in activation pattern with the normal X active, whereas the two other carriers had a random X-inactivation pattern. This family may represent a new phenotype within the EDA-ID disorders. From the heterogeneity in X-inactivation phenotype, we conclude that this mutation is not deleterious enough to be lethal for peripheral blood cells. (c) 2005 Wiley-Liss, Inc.