Molecular pathogenesis of craniosynostosis caused by enhanced BMP signaling

描述（由申请人提供）：颅缝早闭是一种以颅缝过早融合为特征的衰弱性疾病，导致颅骨形状异常、失明和智力迟钝。颅缝早闭症的发病率为每2 500名活产婴儿中有1人，是骨骼系统先天畸形发病率最高的疾病之一。这项研究的长期目标是确定BMP信号传导成分的功能获得性突变导致颅缝早闭的分子机制。最近的研究表明，颅缝早闭与FGF信号转导成分Twist、Msx 2和Efnb 1的突变有关，然而，大多数（70%）颅缝早闭的遗传原因仍然未知。最近提出BMP信号转导参与颅缝早闭。我们开发了一种新的小鼠颅缝早闭模型，其特征是通过BMP信号传导成分中的功能获得性突变导致额缝过早融合。该模型是独特且重要的，因为1）观察到FGF信号传导的上调，2）在融合之前在融合位点处形成异位软骨，以及3）在BMPRIA的杂合无效背景中拯救表型，表明BMP信号传导的精确控制对于预防颅缝早闭至关重要。我们将使用这个模型来研究导致发病机制的分子机制。我们的研究将进一步明确直接参与颅缝过早融合导致颅缝早闭发病机制的分子途径，因此将为人类病例的治疗提供潜在的分子靶点。 公共卫生相关性：在这个建议中，我们将定义BMP信号成分的功能获得性突变导致颅缝早闭的分子机制。大多数（70%）颅缝早闭的遗传原因仍然未知。最近提出BMP信号转导参与颅缝早闭。我们开发了一种新的小鼠颅缝早闭模型，其特征是通过BMP信号传导成分中的功能获得性突变导致额缝过早融合。我们将使用这个模型来研究导致发病机制的分子机制。我们的研究将进一步明确直接参与颅缝过早融合导致颅缝早闭发病机制的分子途径，因此将为人类病例的治疗提供潜在的分子靶点。

DESCRIPTION (provided by applicant): Craniosynostosis is a debilitating condition characterized by premature cranial suture fusion, resulting in abnormal skull shape, blindness and mental retardation. The prevalence of craniosynostosis is at 1 in 2,500 live births, which is one of the highest incidences of congenital malformation of skeletal system. The long-term goal of the proposed studies is to define the molecular mechanism by which gain-of-function mutations in BMP signaling components lead to craniosynostosis. Recent studies demonstrated that craniosynostosis is associated with mutations in FGF signaling components, Twist, Msx2 and Efnb1, however, genetic causes of majority (70%) of craniosynostosis are still unknown. Involvement of BMP signaling to craniosynostosis is recently proposed. We developed a new mouse model for craniosynostosis characterized by premature fusion of a metopic suture by a gain-of-function mutation in a BMP signaling component. This model is unique and important because 1) upregulation of FGF signaling is observed, 2) ectopic cartilage is formed at the site of fusion prior to the fusion, and 3) the phenotype is rescued in heterozygous null background of BMPRIA, indicating that the precise control of BMP signaling is critical to prevent craniosynostosis. We will use this model to investigate molecular mechanisms by which leads to pathogenesis. Our study will further define molecular pathways directly involves in pathogenesis of premature fusion of cranial sutures leading to craniosynostosis, and will therefore provide better insights for potential molecular targets for therapeutic treatment of human cases. PUBLIC HEALTH RELEVANCE: In this proposal, we will define the molecular mechanism by which gain-of-function mutations in BMP signaling components lead to craniosynostosis. Genetic causes of majority (70%) of craniosynostosis are still unknown. Involvement of BMP signaling to craniosynostosis is recently proposed. We developed a new mouse model for craniosynostosis characterized by premature fusion of a metopic suture by a gain-of- function mutation in a BMP signaling component. We will use this model to investigate molecular mechanisms by which leads to pathogenesis. Our study will further define molecular pathways directly involves in pathogenesis of premature fusion of cranial sutures leading to craniosynostosis, and will therefore provide better insights for potential molecular targets for therapeutic treatment of human cases.