Unraveling the mechanisms of prenatal-onset disorders affecting the skeleton

描述(由申请人提供)：骨骼发育不良(SDS)是一组与骨骼异常相关的异质性遗传疾病，会导致幸存者长期的身体残疾，在某些情况下会导致致命的骨骼异常。在过去的30年里，我们收集了18,000多例骨骼发育不良的资料，其中一半以上在产前出现了不同程度的表现。本项目的目的是明确超声、临床、组织学、分子和病理生理学特征的新的或描述不清的产前起病骨骼疾病。该项目的目标是定义和解决 这些疾病的分子基础，从而增加了我们对骨骼发育和生物学的知识，并提高了我们对产前发作性骨骼发育不良的机制和发育过程的理解。我们将通过以下具体目标来实现这些目标：1.定义和描述新的骨骼发育不良。利用大量以前确诊的病例，我们已经确定，大约10%的产前发病的骨骼发育不良不能被指定为特定的诊断。我们将通过定义新的产前起病骨骼疾病来利用这一独特的未分类病例资源。我们将首先集中于表型和分类，定义不明确，但经常遇到的疾病，发现弯曲的骨骼和多个椎体节段缺陷。2.确定新的骨骼发育不良的潜在遗传基础。这一目标将利用目标1中定义的疾病的DNA可获得性，并将使用外显子组测序作为确定其遗传基础的主要方法。外显子组测序数据将根据遗传模式、在选定的有父母血缘的隐性疾病病例中通过纯合性图谱确定的基因座以及在靶组织、生长板软骨和软骨膜/骨膜中的基因表达进行筛选。对于软骨膜/骨膜，我们关于弯曲性骨病的初步数据表明，软骨膜/骨膜中表达的基因对骨骼发育的影响具有重要但尚未被认识的作用。因此，我们预计，我们将描述、定义和解决的许多弯曲骨骼疾病将源于发育中骨骼的这一区域高表达的基因。识别这些研究不足的疾病中的分子缺陷，将得到旨在确定其发病机制的实验的补充，并将提供分子、组织学和临床结构，以了解和分类这一不同的疾病组。拟议工作的预期结果将提高我们对目前描述不佳的产前发作性骨骼疾病的理解。对于普通人群具有重要的医学意义，发现这些产前发病的遗传性骨骼发育不良的基因和途径将确定以前未知的机制和途径，涉及正常生长、骨和软骨内稳以及关节炎和骨质疏松症的发展，从而为制定合理的临床护理和治疗范例提供必要的数据。

DESCRIPTION (provided by applicant): The skeletal dysplasias (SDs) are a heterogeneous group of genetic disorders associated with abnormalities in the skeleton that lead to long-term physical disabilities in survivors and lethal skeletal abnormalities in some cases. Over the last 30 years, we have collected material on more than 18,000 skeletal dysplasia cases, more than half presenting to various degrees in the prenatal period. This project is aimed at defining the ultrasound, clinical, histologic, molecular, and pathophysiologic features of novel or poorly delineated prenatal onset skeletal disorders. The goals of this project are to define and solve the molecular basis of these disorders, thereby increasing our knowledge of skeletal development and biology and improving our understanding of the mechanisms and developmental course of prenatal onset skeletal dysplasias. We will achieve these goals through the following Specific Aims: 1. Define and characterize novel skeletal dysplasias. Using the large number of previously ascertained cases, we have determined that approximately 10% of prenatal onset skeletal dysplasias cannot be assigned a specific diagnosis. We will take advantage of this unique resource of unclassified cases by defining novel prenatal onset skeletal disorders. We will first concentrate on phenotyping and classifying poorly defined, yet frequently encountered, disorders with the findings of bent bones and multiple vertebral segmentation defects. 2. Identify the underlying genetic basis of novel skeletal dysplasias. This Aim will capitalize on the availability of DNA for the disorders defined in Aim 1 and will use exome sequencing as the primary approach to identifying their genetic basis. The exome sequencing data will be filtered based on the pattern of inheritance, loci identified by homozygosity mapping in selected cases of recessive disorders with parental consanguinity, and gene expression in the target tissues, growth plate cartilage and perichondrium/periosteum. For the perichondrium/periosteum, our preliminary data on bent bone disorders have identified an important yet unappreciated role for the effects of genes expressed in perichondrium/periosteum on skeletal development. It is thus our expectation that many of the bent bone disorders that we will characterize, define and solve will result from genes with high expression in this region of the developing skeleton. Identifying the molecular defect in these understudied disorders, will be complemented by experiments aimed at determining their pathogenetic mechanisms, and will provide molecular, histologic and clinical structures within which to understand and classify this diverse group of disorders. The expected outcomes of the proposed work will improve our understanding of currently poorly delineated prenatal onset skeletal disorders. Of medical importance to the general population, discovering the genes and pathways in these prenatal onset genetic skeletal dysplasias will identify previously unknown mechanisms and pathways involved in normal growth, bone and cartilage homeostasis and the development of arthritis and osteoporosis, thus providing essential data for developing rational clinical care and treatment paradigms.