Hypertrophic cardiomyopathy: from mutation to functional analysis of defective protein
Hypertrophic cardiomyopathy: from mutation to functional analysis of defective protein
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DOI：
10.3325/cmj.2011.52.384
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发表时间：
2011-06-01
影响因子：
1.9
通讯作者：
Brdicka, Radim
中科院分区：
文献类型：
--
作者：
Capek, Pavel;Vondrasek, Jiri;Brdicka, Radim
目的 从分子遗传学的角度分析大量患者肥厚型心肌病的发病机制，并对缺陷型肌球蛋白 7 蛋白的 3D 分子模型进行计算机功能分析。 方法 本研究纳入了来自捷克共和国不同地区的 153 名确诊肥厚型心肌病患者。对 DNA 样本进行了 MYH7 基因外显子 21 和 22 突变的分析，这些突变与高突变聚类相关。以无核苷酸扇贝肌球蛋白S1的X射线结构为结构模板，构建了人肌球蛋白7的3D模型。我们对肌球蛋白 7 蛋白 769-788 个氨基酸区域的突变型和野生型肽进行了从头结构预测。结果 在 2 名不相关的严重肥厚型心肌病患者中发现了 Arg(870)His 和 Asp(778)Val 氨基酸改变。选择 Asp(778)Val 变体用于后续的计算机 3D 分子建模。 Val对Asp的突变不仅改变了与其他氨基酸或离子的相互作用模式的特征，而且Val作为一种小的疏水性氨基酸，也可以彻底改变该区域的稳定性。 结论 MYH7基因的突变位置和氨基酸组成的变化可能对肥厚型心肌病患者的疾病结局产生至关重要的负面影响。此外，改变氨基酸电荷的突变比保守突变更有可能影响蛋白质功能。
Aim To analyze the genesis of hypertrophic cardiomyopathy on a large cohort of patients from molecular genetics point of view and perform the functional analysis of the 3D molecular model of defective myosin-7 protein in silico.Methods The study enrolled 153 patients with diagnosed hypertrophic cardiomyopathy from different parts of the Czech Republic. DNA samples were analyzed for mutations in exons 21 and 22 of the MYH7 gene, which have been associated with high mutation clustering. The 3D model of human myosin-7 was built using the x-ray structure of nucleotide-free scallop myosin S1 as the structural template. We performed de novo structure prediction of mutant and wild type peptides spanning the 769-788 amino acids region of the myosin-7 protein.Results The Arg(870)His and Asp(778)Val amino acid alterations were found in 2 unrelated patients with a severe form of hypertrophic cardiomyopathy. The Asp(778)Val variation was chosen for subsequent 3D molecular modeling in silico. The mutation of the Asp by Val not only changes the character of the interaction pattern with other amino acids or ions but Val, being a small hydrophobic amino acid, can also completely change the stability of the region.Conclusion Mutation location in the MYH7 gene and changes in amino acid composition may have a crucial negative impact on the outcome of the disease in patients with hypertrophic cardiomyopathy. In addition, a mutation that changes the charge of the amino acid is more likely to affect protein function than a conservative mutation.