SOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype-Phenotype Correlations
SOS1 Mutations in Noonan Syndrome: Molecular Spectrum, Structural Insights on Pathogenic Effects, and Genotype-Phenotype Correlations
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DOI：
10.1002/humu.21492
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发表时间：
2011-07-01
期刊：
影响因子：
3.9
通讯作者：
Tartaglia, Marco
中科院分区：
文献类型：
--
作者：
Lepri, Francesca;De Luca, Alessandro;Tartaglia, Marco
努南综合征（NS）是影响发育和生长的最常见的非染色体疾病之一。NS是由异常的RAS-MAPK信号传导引起的，并且是遗传异质性的，这部分地解释了该孟德尔性状记录的显著临床变异性。最近，我们和其他人确定SOS 1作为一个主要的基因基础NS。在这里，我们进一步探索了SOS 1突变谱及其相关的表型特征。整个SOS 1编码序列的突变扫描允许鉴定33种被认为具有病理学意义的不同变体，包括16种新的错义变化和框内插入缺失。鉴定了各种突变簇，这些突变簇使预测在结构上有助于维持自身抑制的蛋白质区域不稳定或改变方向。两个以前不受重视的集群预测，以提高SOS 1的招聘质膜，从而促进空间重新定位的结构域有助于抑制，也被确认。基因型-表型分析证实了我们以前的观察，建立了高频率的外胚层异常和低患病率的认知功能障碍和减少的增长。最后，对非综合征性肺动脉狭窄、房间隔缺损和室间隔缺损患者进行的突变分析排除了生殖系SOS 1病变对这些心脏异常孤立发生的主要贡献。Mutat 32：760-772，2011. (C)2011 Wiley-Liss，Inc.
Noonan syndrome (NS) is among the most common nonchromosomal disorders affecting development and growth. NS is caused by aberrant RAS-MAPK signaling and is genetically heterogeneous, which explains, in part, the marked clinical variability documented for this Mendelian trait. Recently, we and others identified SOS1 as a major gene underlying NS. Here, we explored further the spectrum of SOS1 mutations and their associated phenotypic features. Mutation scanning of the entire SOS1 coding sequence allowed the identification of 33 different variants deemed to be of pathological significance, including 16 novel missense changes and in-frame indels. Various mutation clusters destabilizing or altering orientation of regions of the protein predicted to contribute structurally to the maintenance of autoinhibition were identified. Two previously unappreciated clusters predicted to enhance SOS1's recruitment to the plasma membrane, thus promoting a spatial reorientation of domains contributing to inhibition, were also recognized. Genotype-phenotype analysis confirmed our previous observations, establishing a high frequency of ectodermal anomalies and a low prevalence of cognitive impairment and reduced growth. Finally, mutation analysis performed on cohorts of individuals with nonsyndromic pulmonic stenosis, atrial septal defects, and ventricular septal defects excluded a major contribution of germline SOS1 lesions to the isolated occurrence of these cardiac anomalies. Hum Mutat 32:760-772, 2011. (C) 2011 Wiley-Liss, Inc.