The Effect of Single Nucleotide Polymorphisms on Protein Structure and Interactio

描述（由申请人提供）： 人类DNA序列在个体之间存在差异，最常见的变异被称为单核苷酸多态性或SNP。研究表明，非同义编码SNP（nsSNPs -发生在蛋白质编码区中导致氨基酸取代的SNP）可以导致许多人类疾病。X连锁精神发育迟滞（XLMR）是一组异质性疾病的一个特殊例子，估计在精神发育迟滞人群中的发生率为5-12%。具体来说，在这个建议中，我们专注于XLMR所造成的缺陷，在spearmine合酶（SMS）。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，对细胞的正常生长和分化至关重要。特别是已经显示出，绿鱼胺调节特定细胞中的离子通道活性。在本研究中，我们将研究SMS中已知导致XLMP的三个nsSNP，以揭示突变对SMS结构，功能和相互作用影响的分子机制。我们的合作者Schwartz博士和同事证明，在编码366个氨基酸的蛋白质的spearmine合成酶基因中的三个nsSNP（G56 S、V132 G和I150 T）负责XLMR。然而，没有对分子水平的影响的解释。因此，通过在分子水平上的计算建模与Schwartz博士实验室中的实验研究的结合努力对这些变体的进一步研究将提供这些snSNP如何影响spearnime合酶稳定性、功能和相互作用的分子基础的有价值的信息。拟议研究的结果有可能为了解疾病的原因提供有价值的见解。该项目将使PI的实验室通过与格林伍德遗传中心（Charles Schwartz博士）合作进入临床研究领域。计算模型的结果将被用来产生可检验的假设和其他仍然未知的错义突变将被建议。这些假设和突变体将在Schwartz博士实验室进行生化测试，并根据可用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.