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首页> 外文期刊>Journal of genetics >In silico analysis of the effects of disease-associated mutations of beta-hexosaminidase A in Tay-Sachs disease
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In silico analysis of the effects of disease-associated mutations of beta-hexosaminidase A in Tay-Sachs disease

机译：β-己氨基氨基氨基氨基氨基氨基氨基酶A中β-己氨基氨基氨基酶A中的疾病相关突变效果的硅藻分析

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摘要

Tay-Sachs disease (TSD), a deficiency of beta-hexosaminidase A (Hex A), is a rare but debilitating hereditary metabolic disorder. Symptoms include extensive neurodegeneration and often result in death in infancy. We report an in silico study of 42 Hex A variants associated with the disease. Variants were separated into three groups according to the age of onset: infantile (n=28), juvenile (n=9) and adult (n=5). Protein stability, aggregation potential and the degree of conservation of residues were predicted using a range of in silico tools. We explored the relationship between these properties and the age of onset of TSD. There was no significant relationship between protein stability and disease severity or between protein aggregation and disease severity. Infantile TSD had a significantly higher mean conservation score than nondisease associated variants. This was not seen in either juvenile or adult TSD. This study has established that the degree of residue conservation may be predictive of infantile TSD. It is possible that these more highly conserved residues are involved in trafficking of the protein to the lysosome. In addition, we developed and validated software tools to automate the process of in silico analysis of proteins involved in inherited metabolic diseases. Further work is required to identify the function of well-conserved residues to establish an in silico predictive model of TSD severity.
机译：Tay-Sachs病（TSD）是一种缺乏β-己糖胺酶a（Hex a）的疾病，是一种罕见但使人衰弱的遗传性代谢障碍。症状包括广泛的神经退行性变，通常会导致婴儿死亡。我们报告了42个与该疾病相关的Hex A变异的电子研究。根据发病年龄将变异分为三组：婴儿组（n=28）、青少年组（n=9）和成人组（n=5）。使用一系列电子工具预测蛋白质稳定性、聚集潜力和残留物的保守性。我们探讨了这些特性与TSD发病年龄之间的关系。蛋白质稳定性与疾病严重程度或蛋白质聚集与疾病严重程度之间没有显著关系。婴儿型TSD比非疾病相关变异体的平均保守性得分显著更高。这在青少年或成人TSD中均未发现。这项研究已经证实，残留保存的程度可以预测婴儿TSD。这些高度保守的残基可能参与了蛋白质向溶酶体的运输。此外，我们开发并验证了软件工具，以自动化遗传代谢疾病相关蛋白质的电子分析过程。为了建立TSD严重程度的电子预测模型，需要进一步的工作来确定保存良好的残基的功能。

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