The Effect of Single Nucleotide Polymorphisms on Protein Structure and Interactio

描述(由申请人提供)： 人类DNA序列因个体而异，最常见的变异称为单核苷酸多态(SNPs)。研究表明，非同义编码的SNPs(nsSNPs-发生在蛋白质编码区的导致氨基酸替换的SNPs)可导致许多人类疾病。X-连锁精神发育迟滞(XLMR)是一组异质性疾病的特例，估计在智力低下人群中的发生率为5%-12%。具体地说，在这个提案中，我们将重点放在由矛胺合成酶(SMS)缺陷引起的XLMR上。多胺是一种普遍存在的分子，它与细胞中的各种其他分子相互作用，是细胞正常生长和分化所必需的。尤其是鱼腥草胺已被证明是调节离子通道活动的特殊细胞。在这个提案中，我们将研究Sms中已知的导致XLMP的三个nsSNP，以揭示突变对Sms的结构、功能和相互作用的影响的分子机制。我们的合作者Schwartz博士和他的同事发现，编码366个氨基酸的矛胺合成酶基因中的三个nsSNPs(G56S、V132G和I150T)是导致XLMR的原因。然而，在分子水平上的影响还没有得到解释。因此，通过分子水平的计算建模和Schwartz博士实验室的实验研究相结合的方式进一步研究这些变体，将为这些SnSNP如何影响spearnime合成酶的稳定性、功能和相互作用提供有价值的分子基础信息。拟议的研究结果有可能为理解疾病的原因提供有价值的见解。该项目将通过与格林伍德遗传中心(Charles Schwartz博士)合作，使Pi的实验室能够进入临床研究领域。计算模型的结果将被用来产生可测试的假设，并将提出其他仍未知的错义突变。这些假说和突变体将在施瓦茨博士的实验室进行生化测试，并根据现有的临床数据进行筛选。

DESCRIPTION (provided by applicant): Human DNA sequence differs among individuals and the most common variations are known as single nucleotide polymorphisms, or SNPs. Studies have shown that non-synonymous coding SNPs (nsSNPs - SNPs occurring in protein coding regions which lead to amino acid substitutions) can be responsible for many human diseases. X-linked mental retardation (XLMR) is a particular example of a group of heterogeneous conditions with an estimated frequency of 5-12% in the mentally retarded populations. Specifically, in this proposal we focus on XLMR caused by a defect in spearmine synthase (SMS). Polyamines are ubiquitous molecules that interact with variety of other molecules in the cell and are essential for normal cell growth and differentiation. Especially spearmine have been shown to modulate ion channel activities is particular cells. In this proposal we will investigate three nsSNP within SMS known to cause XLMP to reveal the molecular mechanism of effect of mutations on structure, function and interactions of SMS. Three nsSNPs (G56S, V132G and I150T) in the spearmine sythase gene that encodes a protein of 366 amino acids were shown to be responsible for XLMR by our collaborator Dr. Schwartz and co-workers. However, no explanation of the effects on molecular level is available. Therefore, further investigation of these variants by combined efforts of computational modeling at molecular level with experimental investigations in Dr. Schwartz lab will provide valuable information of the molecular basis of how these snSNP affect the spearnime synthase stability, function and interactions. The outcome of the proposed research has the potential to provide valuable insights towards understanding the cause of the disease. The project will enable PI's lab to enter the field of the clinical research by collaborating with the Greenwood Genetic Center (Dr. Charles Schwartz). The results of the computational modeling will be used to generate testable hypothesizes and other still unknown missense mutations will be suggested. These hypotheses and mutants will be biochemically tested in Dr. Schwartz lab and screened against available clinical data.