Mechanisms of craniofrontonasal syndrome: toward a rational therapeutic strategy

描述(申请人提供)：颅咽综合征(CFNS)是一种X连锁疾病，影响颅面发育的多个方面，由EFNB1基因突变引起。额鼻发育不良是CFNS的一个定义属性，但在此背景下ePhin-B1功能的发育病因尚未完全确定。我们建议利用小鼠作为一个模型来了解EFNB1控制面中部发育的基本发育机制。CFNS是一种罕见的疾病，因为EFNB1是一种X连锁基因，杂合子女性比半合子男性更容易受到影响。这与杂合子的雌性代表表达和不表达ePhin-B1的细胞的镶嵌有关。结合小鼠遗传学和分子生物学的方法，我们将确定这种现象的机制基础。最后，我们提出了一种可能的预防CFNS的一般策略，我们将开始在小鼠模型中测试其可行性。

DESCRIPTION (provided by applicant): Craniofrontonasal syndrome (CFNS) is an X-linked disease that affects multiple aspects of craniofacial development and is caused by mutations in the EFNB1 gene. Frontonasal dysplasia is a defining attribute of CFNS, but the developmental etiology underlying ephrin-B1 function in this context is incompletely defined. We propose to utilize the mouse as a model to understand the basic developmental mechanisms by which EFNB1 acts to control development of the midface. CFNS is an unusual disease in that whereas EFNB1 is an X-linked gene, heterozygous females are more severely affected than hemizygous males. This is related to the fact that heterozygous females represent a mosaic of ephrin-B1 expressing and non-expressing cells. Using a combination of mouse genetics and molecular biology approaches, we will define the mechanistic basis for this phenomenon. Finally, we propose a possible general strategy for preventing CFNS, whose feasibility we will begin to test in a mouse model.