PHENOGENETICS OF SKULL AND BRAIN INTEGRATION IN CRANIOSYNOSTOSIS

描述(申请人提供)：颅缝融合，一个或多个颅缝的过早融合，是一种常见的畸形，每2500名活产中就有一名发生，并表现出显著的表型变异。颅缝融合症的颅骨形态不能简单地用缝线过早融合来解释，而是涉及到广泛的头部发育异常。现在已经确定了一些突变，这些突变与某些临床定义的颅缝早闭症有关。包括Crouzon综合征、Apert综合征和Pfeiffer综合征在内的8种颅突融合疾病是由成纤维细胞生长因子受体(FGFR)-1、-2或-3突变引起的。FGFR酪氨酸激酶及其配体在细胞的发育过程中发挥着基础和广泛的作用，并通过激活多条通路和信号通路之间的相互作用，在控制细胞的迁移、增殖、分化和生存方面发挥关键作用。重要的是，FGFRs参与了头骨、脑膜和大脑的发育。我们提出了一项分子和形态研究的统一研究，旨在确定颅突融合症的基因-表型连续体中的中间发育步骤。我们的方法是一种“表型遗传”方法，它试图将生物表型与其潜在的遗传过程联系起来，例如通过激活信号来实现区域分化。通过对孤立性颅缝早闭患者的MR和CT影像档案的研究，我们确定了孤立性和综合征性颅缝早闭患者头骨和脑的特征的表型相关性。这些相关性表明大脑和头骨之间存在着强烈的发育关联。这些相关性将使用来自冠状颅缝早闭和Apert、Crouzon和Pfeiffer综合征病例的CT和MR图像以及针对这些综合征的两个FGFR2小鼠模型的Micro-CT和Micro-MR图像的额外3D数据进一步测试。利用我们对人类头骨和大脑协同变异的研究确定的解剖位置作为时间和空间指南，我们将记录FGFR2/S252W和FgfrcC342Y/突变小鼠在三个发育阶段的发育中颅骨组织中异常增殖、分化、细胞凋亡和FGF/FGFR信号的模式。我们的假设是，成形期颅脑中异常的成纤维细胞生长因子/成纤维细胞生长因子受体信号的时空图是一系列发育事件的基础，这些事件导致这些部位局部异常的细胞过程，最终导致颅缝融合时头部和脑形状的异常。我们的形态分析将为我们的分子研究提供信息，即两个特定的突变如何影响表型发生过程，以产生导致颅突融合表型的发育关系。公共卫生相关性：颅骨融合是一种常见的畸形，其定义是颅骨过早融合，最常见的是头盖骨。我们的目标是使用来自患有非综合征冠状颅缝融合和Apert、Crouzon和Pfeiffer综合征的人类群体的数据，以及来自Apert和Crouzon综合征的小鼠模型的数据，来研究颅缝融合症中头骨和大脑发育的整合性质，以了解在这些疾病中整个头部的产生，而不仅仅是闭合缝合。

DESCRIPTION (provided by applicant): Craniosynostosis, the premature fusion of one or more cranial sutures, is a common malformation occurring in 1 out of every 2500 live births and shows marked variation of phenotypes. The skull shape in craniosynostosis can not be explained simply by the premature fusion of sutures, but involves widespread abnormal development of the head. A number of mutations have now been identified that are associated with certain clinically defined craniosynostosis conditions. Eight of the craniosynostosis disorders including Crouzon, Apert and Pfeiffer syndromes are caused by mutations in fibroblast growth factor receptors (FGFR)-1, -2 or -3. FGFR tyrosine kinases and their ligands play fundamental and widespread roles in development and are known to play a crucial role in the control of cell migration, proliferation, differentiation and survival by activation of multiple pathways and interaction among signaling pathways. Importantly, FGFRs are involved in development of the skull, meninges, and the brain. We propose a unifying study of molecular and morphological research aimed at identifying the intermediate developmental steps in the genotype-phenotype continuum of craniosynostosis. Ours is a "phenogenetic" approach that attempts to connect biological phenotypes with their underlying genetic processes such as regional differentiation by activation of signaling. Through a study of archived MR and CT images of humans with isolated craniosynostosis we defined phenotypic correlations of traits on skull and brain in isolated and syndromic craniosynostosis. These correlations are indicative of strong developmental associations between brain and skull. These associations will be further tested using additional 3D data from CT and MR images of cases of coronal craniosynostosis and Apert, Crouzon and Pfeiffer syndromes and micro-CT and micro-MR of two Fgfr2 mouse models for these syndromes. Using anatomical sites identified by our investigations of human skull and brain covariation as a temporal and spatial guide, we will document patterns of abnormal proliferation, differentiation, apoptosis, and Fgf/Fgfr signaling in developing cranial tissues of Fgfr2+/S252W and FgfrcC342Y/+ mutant mice at three developmental stages. Our hypothesis is that the spatiotemporal map of abnormal Fgf/Fgfr signaling in formative skull and brain is the basis for a series of developmental events that result in anomalous cellular processes local to those sites and ultimately result in the abnormal head and brain shape in craniosynostosis. Our morphological analyses will inform our molecular investigations of how two particular mutations affect phenogenetic processes to produce developmental relationships that lead to craniosynostosis phenotypes. PUBLIC HEALTH RELEVANCE: Craniosynostosis is a common malformation which is defined by the premature fusion of skull bones, most commonly those of the calvaria. Our aims are to study the integrated nature of skull and brain development in craniosynostosis using data from human populations with nonsyndromic coronal craniosynostosis and Apert, Crouzon and Pfeiffer syndrome, as well as data from mouse models for Apert and Crouzon syndrome to understand the production of the entire head in these disorders and not just the closed suture.