Identifying the pathological mechanism of polyalanine expansion mutations in the X-linked Hypopituitarism gene SOX3

智力迟钝（MR）是一种使人衰弱的疾病，影响着1-3%的人口。在许多情况下，核磁共振是由出生前调节大脑发育的基因的变化（突变）引起的。我们正在研究一种被称为x连锁垂体功能减退症（XH）的遗传性MR的家庭，其中只有男孩会受到影响。除了智力障碍外，患有XH的男孩还有垂体功能差，导致身材矮小和新陈代谢缓慢。在严重的情况下，脑垂体没有完全形成，这些婴儿病得很重，在某些情况下无法生存。我们之前已经证明，XH是由于SOX3基因的异常变化，其中连续丙氨酸残基的数量增加到临界阈值以上（多丙氨酸扩增突变）。最近在其他几个基因中也发现了类似的突变，这些基因也会导致严重的出生缺陷。然而，目前对多丙氨酸扩增突变如何导致这些疾病知之甚少。这项提议的总体目标是为这种疾病产生一个小鼠模型。对这些小鼠的分析将帮助我们回答关于这种疾病的许多未解决的问题，包括：突变蛋白是如何引起这种疾病的？大脑和垂体的哪些部分受到影响，它们的功能是如何改变的？突变蛋白如何影响细胞中的其他基因和蛋白质？最终，我们希望这个小鼠模型将帮助我们开发新的和改进的XH和其他由丙氨酸扩增突变引起的疾病的治疗方法。

Mental retardation (MR) is a debilitating disorder which affects 1-3% of the population. In many cases, MR results from changes (mutations) in genes which regulate the development of the brain before birth. We are studying families with an inherited form of MR termed X-linked Hypopituitarism (XH) in which only boys are affected. In addition to intellectual disability, boys with XH also have poor pituitary function resulting in short stature and slow metabolism. In severe cases, where the pituitary has failed to form completely, these babies are extremely ill and in some instances do not survive. We have previously shown that XH is due to an unusual change in the SOX3 gene in which the number of consecutive alanine residues is increased above a critical threshold (polyalanine expansion mutations). Similar mutations have recently been identified in several other genes that also cause severe birth defects. However, little is currently known about how polyalanine expansion mutations cause these disorders. The overall aim of this proposal is generate a mouse model for this disorder. Analysis of these mice will help us to answer many unresolved questions about this disorder including: How does the mutant protein cause this disorder? Which parts of the brain and pituitary are affected and how is their function altered? How does the mutant protein affect other genes and proteins in the cell? Ultimately, we hope that this mouse model will help us to develop new and improved therapies for XH and other disorders that are caused by alanine expansion mutations.