Functional variants of RUNX2 related to bone density

RUNX2 与骨密度相关的功能变异

• 批准号: nhmrc : 428237
• 负责人: A/Pr Nigel Morrison
• 金额: $ 30.14万
• 依托单位: Griffith University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/functional-variants-runx2-bone-density/95215
• 关键词: Functional; variants; RUNX2; related; bone

Bone density and osteoporosis have a genetic component. Identifying genes that are involved in determining bone density may permit advances in controlling osteoporosis. We have identified a variant in a gene called RUNX2 that is related to bone density high enough to protect individuals four fold against Colle's fracture, the common wrist fracture seen in women. This variant is highly correlated with changes in the second promoter of RUNX2, such that the high bone density form appears to be the ancestral form of this gene. We now need to know how this change in this promoter alters bone density and we are following up on observations that other important transcription factors bind to the variable site in the promoter. Furthermore, we have assembled a large collection of samples from people who have had extensive measures of bone density and arthritis in order to accurately measure the impact of this gene on bone density, osteoarthritis and bone fracture. In addition, some people with bone fracture at the hip, or low bone density, have mutations in this gene. Such mutations in a region called the Q-repeat are rather common, 1-200 people are carriers. Our data show that these mutant proteins are not as efficient at their task of regulating other genes. We now want to know how this occurs in a molecular sense, since it is known that the Runx2 protein resides in the nucleus of the cell and interacts with many other regulators. This part of the project is being done with one of the world experts on gene regulation in bone cells. Since RUNX2 is a master regulator of the cells that make bone, this gives hope that it may be possible to alter bone formation through this master regulator.

骨密度和骨质疏松症有遗传因素。确定参与决定骨密度的基因可能有助于控制骨质疏松症。我们已经确定了一种名为RUNX 2的基因变体，该基因与骨密度相关，足以保护个体免受Colle骨折的四倍，Colle骨折是女性常见的手腕骨折。这种变异与RUNX 2第二启动子的变化高度相关，因此高骨密度形式似乎是该基因的祖先形式。我们现在需要知道这个启动子中的这种变化如何改变骨密度，我们正在跟踪观察其他重要的转录因子与启动子中的可变位点结合。此外，我们已经收集了大量的样本，这些样本来自于对骨密度和关节炎进行了广泛测量的人，以准确测量该基因对骨密度、骨关节炎和骨折的影响。此外，一些髋部骨折或骨密度低的人，这种基因也会发生突变。这种突变在一个称为Q重复的区域是相当常见的，1-200人是携带者。我们的数据表明，这些突变蛋白在调节其他基因的任务中没有那么有效。我们现在想知道这在分子意义上是如何发生的，因为已知Runx 2蛋白存在于细胞核中，并与许多其他调节因子相互作用。该项目的这一部分是由一位世界骨细胞基因调控专家完成的。由于RUNX 2是制造骨骼的细胞的主调节器，这给了人们希望，通过这个主调节器改变骨形成是可能的。