SINGLE SUTURE CRANIOSYNOSTOSIS: CANDIDATE GENE AND PATHWAY DISCOVERY

描述（由申请人提供）：颅缝早闭是颅骨的病理性融合。在过去的十年中，我们对颅缝早闭引起的多种畸形综合征的认识取得了重大进展。已显示成纤维细胞生长因子受体（FGFR 1 -3）、TWIST 1、MSX 2和EFNB 1中的突变各自引起人类颅缝早闭综合征。在几个国际实验室开展的这项广泛的工作，极大地影响了我们诊断和咨询综合征性颅缝早闭症家庭的方式。尽管有关综合征形式的知识迅速增长，孤立的骨性结合的原因仍然难以捉摸。虽然比综合征形式更常见，但相对较少的研究集中在孤立性颅缝早闭的分子发病机制上。这组颅骨畸形的频率，需要复杂的手术治疗及其相关的发病率，使孤立的颅缝早闭症的候选人进行深入的科学研究。我们建议使用三种方法来识别和表征孤立性颅缝早闭症的候选遗传原因：高通量基因组测序，大规模微阵列表达分析和发育基因表达。我们利用从正常颅骨发育和综合征形式的颅缝早闭的研究中获得的知识，发展了两个相互关联的假设：（A）两类基因中的罕见序列变异导致孤立的颅缝早闭：调节缝发育的基因和突变时引起综合征性颅缝早闭的基因;和（B）涉及颅缝发育的遗传途径和综合征性颅缝早闭中受影响的遗传途径在孤立的非综合征性颅缝早闭中受到类似的影响。在这个建议中，我们描述了一系列的实验，旨在通过鉴定罕见的遗传变异，改变颅骨成骨细胞基因表达，以及候选基因的时空表达来发现孤立性颅缝早闭的潜在分子原因。我们的研究团队的专业知识和互补的高通量方法的可用性，允许开发一个孤立的颅缝早闭症的遗传和发育发病机制的全面调查。

DESCRIPTION (provided by applicant): Craniosynostosis is the pathologic fusion of the calvaria. Over the past ten years significant advances have been made in our understanding of multiple malformation syndromes that involve craniosynostosis. It has been shown that mutations in the fibroblast growth factor receptors (FGFR1-3), TWIST1, MSX2, and the EFNB1 each cause craniosynostosis syndrome in humans. This extensive body of work, carried out in several international laboratories, has significantly impacted how we diagnose and counsel families with syndromic craniosynostosis. Despite the rapid growth of knowledge regarding syndromic forms, the causes of isolated synostosis remain elusive. Though vastly more common than syndromic forms, relatively little research has focused on the molecular pathogenesis of isolated craniosynostosis. The frequency of this group of calvarial malformations, the need for complex surgical management and its associated morbidity make isolated craniosynostosis a candidate for intense scientific investigation. We propose the use of three approaches to identify and characterize candidate genetic causes of isolated craniosynostosis: high throughput genomic sequencing, large-scale microarray expression analysis, and developmental gene expression. We have used knowledge gained from the investigation of normal calvarial development and syndromic forms of craniosynostosis to develop two interrelated hypotheses: (A) Rare sequence variants in two classes of genes result in isolated craniosynostosis: those that regulate suture development and those that, when mutated, cause syndromic craniosynostosis; and (B) Genetic pathways involved in cranial suture development and those impacted in the syndromic craniosynostoses are similarly affected in isolated, non-syndromic craniosynostosis. In this proposal, we describe a series of experiments designed to discover potential molecular causes of isolated craniosynostosis through the identification of rare genetic variants, altered calvarial osteoblast gene expression, and the temporal and spatial expression of candidate genes. The expertise of our research team and the availability of complementary high throughput approaches has allowed for the development of a comprehensive investigation of the genetic and developmental pathogenesis of isolated craniosynostosis.