Identification of Four Novel PCDH19 Mutations and Prediction of Their Functional Impact
Identification of Four Novel PCDH19 Mutations and Prediction of Their Functional Impact
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DOI：
10.1111/ahg.12082
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发表时间：
2014-11-01
影响因子：
1.9
通讯作者：
Murgia, Alessandra
中科院分区：
文献类型：
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作者：
Leonardi, Emanuela;Sartori, Stefano;Murgia, Alessandra
PCDH 19基因编码原钙粘蛋白-19，一种具有六个钙粘蛋白（EC）结构域的跨膜蛋白，含有可能参与神经元连接的粘附界面。在患有癫痫的女孩中已经确定了一百多个主要是私人突变，有或没有智力残疾（ID）。此外，传播性半合子男性没有癫痫发作或ID，使得难以确定新鉴定的变体的致病性。在这里，我们描述了一个综合的方法来评估四个新的PCDH 19突变的致病性。分离分析已经补充了在蛋白质水平上的突变效应的计算机模拟分析。使用序列信息，我们比较了不同的计算预测方法。我们使用同源建模来构建两个PCDH 19 EC结构域的结构模型，并比较野生型和突变型模型，以确定模型表面的残基相互作用或生化特性的差异。我们的分析表明，新的突变在发挥其致病作用的不同分子效应。其中两个干扰或改变预测介导配体或蛋白质结合的功能残基，一个改变EC结构域折叠稳定性;移码突变产生缺乏胞内结构域的截短蛋白质。有趣的是，携带假定的功能丧失突变的女孩表现出最严重的表型。
The PCDH19 gene encodes protocadherin-19, a transmembrane protein with six cadherin (EC) domains, containing adhesive interfaces likely to be involved in neuronal connection. Over a hundred mostly private mutations have been identified in girls with epilepsy, with or without intellectual disability (ID). Furthermore, transmitting hemizygous males are devoid of seizures or ID, making it difficult to establish the pathogenic nature of newly identified variants. Here, we describe an integrated approach to evaluate the pathogenicity of four novel PCDH19 mutations. Segregation analysis has been complemented with an in silico analysis of mutation effects at the protein level. Using sequence information, we compared different computational prediction methods. We used homology modeling to build structural models of two PCDH19 EC-domains, and compared wild-type and mutant models to identify differences in residue interactions or biochemical properties of the model surfaces. Our analysis suggests different molecular effects of the novel mutations in exerting their pathogenic role. Two of them interfere with or alter functional residues predicted to mediate ligand or protein binding, one alters the EC-domain folding stability; the frame-shift mutation produces a truncated protein lacking the intracellular domain. Interestingly, the girl carrying the putative loss of function mutation presents the most severe phenotype.