Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features
Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features
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DOI：
10.1038/jhg.2012.7
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发表时间：
2012-03-01
影响因子：
3.5
通讯作者：
Matsumoto, Naomichi
中科院分区：
文献类型：
--
作者：
Yoneda, Yuriko;Saitsu, Hirotomo;Matsumoto, Naomichi
Sotos综合征的特征是产前和产后过度生长，特征性颅面特征和智力低下。NSD 1的单倍不足导致Sotos综合征。最近，在三个具有Sotos样过度生长特征的个体中发现了两个包含核因子I-X（NFIX）的微缺失和一个NFIX无义突变，这表明NFIX异常可能参与了Sotos样特征。有趣的是，在9名马歇尔-史密斯综合征患者中也发现了NFIX的7个移码突变和2个剪接位点突变。在这项研究中，48名疑似Sotos综合征但未显示NSD 1异常的个体通过高分辨率熔解分析检查了NFIX突变。我们在NFIX蛋白的DNA结合/二聚化结构域中鉴定了两个杂合错义突变。这两个突变都发生在进化保守的氨基酸上。c.179T > C（p.Leu60Pro）突变发生于新生，c.362G > C（p.Arg121Pro）突变遗传自可能受影响的母亲。这两种突变在250名健康的日本对照中均不存在。我们的研究表明，NFIX的错义突变能够导致Sotos样特征。NFIX蛋白的DNA结合/二聚化结构域的突变也表明，由于NFIX异常，转录调控异常波动。在具有与NSD 1变化无关的Sotos样特征的个体中，应考虑进行NFIX基因检测。Journal of Human Genetics（2012）57，207-211; doi：10.1038/jhg.2012.7; 2012年2月2日在线发表
Sotos syndrome is characterized by prenatal and postnatal overgrowth, characteristic craniofacial features and mental retardation. Haploinsufficiency of NSD1 causes Sotos syndrome. Recently, two microdeletions encompassing Nuclear Factor I-X (NFIX) and a nonsense mutation in NFIX have been found in three individuals with Sotos-like overgrowth features, suggesting possible involvements of NFIX abnormalities in Sotos-like features. Interestingly, seven frameshift and two splice site mutations in NFIX have also been found in nine individuals with Marshall-Smith syndrome. In this study, 48 individuals who were suspected as Sotos syndrome but showing no NSD1 abnormalities were examined for NFIX mutations by high-resolution melt analysis. We identified two heterozygous missense mutations in the DNA-binding/dimerization domain of the NFIX protein. Both mutations occurred at evolutionally conserved amino acids. The c.179T > C (p.Leu60Pro) mutation occurred de novo and the c.362G > C (p.Arg121Pro) mutation was inherited from possibly affected mother. Both mutations were absent in 250 healthy Japanese controls. Our study revealed that missense mutations in NFIX were able to cause Sotos-like features. Mutations in DNA-binding/dimerization domain of NFIX protein also suggest that the transcriptional regulation is abnormally fluctuated because of NFIX abnormalities. In individuals with Sotos-like features unrelated to NSD1 changes, genetic testing of NFIX should be considered. Journal of Human Genetics (2012) 57, 207-211; doi:10.1038/jhg.2012.7; published online 2 February 2012