Feline Model of an Inherited Craniofacial Abnormality

描述(申请人提供)：人类和其他生物的头面部异常是常见的出生缺陷，尽管很少是可遗传的。大多数关于身体和面部基本结构发育的研究都是从低等生物，如果蝇和斑马鱼来解释的。与老鼠不同，猫被强烈地选为面部结构。在进化上，猫科动物与人类的亲缘关系比与老鼠的亲缘关系更近，它们的基因组结构相似。因此，将影响猫颅面结构正常和异常发育过程的基础和临床研究转移到人类身上将是非常有效的。这项研究的长期目标是了解人类头面部发育的遗传成分。主要目标是将这只猫培育成人类面部发育的模型。缅甸猫有一个单一的基因缺陷，会导致面部上颌区域的重复。与其他目前的动物模型相比，猫科动物面部发育的突变和基因的相互作用将更类似于人类。将使用三种方法来开发该模型。具体目的1：从猫BAC文库中分离猫发育基因和基因相关微卫星的同源物。HOX基因簇和Sonic Hedgehog基因已被证明强烈影响面部发育。假设是这些基因中的一个导致了猫咪的面部缺陷。与基因并列的高度多态的微卫星标记也将从猫身上分离出来。具体目标2：扫描Sonic Hedgehog以寻找致病突变。声波刺猬对上颌骨有很强的影响。具体目标3：猫科动物家系的连锁分析。基因相关标记将在以前收集的分离出颅面部缺陷的猫科动物家庭中进行分析。这种方法将支持候选基因的努力。这个假设是，连锁分析将确定候选基因的染色体区域，重点是搜索候选基因。一旦确定，对猫或其他物种中这些基因的突变分析将有助于理解人类面部发育的遗传学。

DESCRIPTION (provided by applicant): Craniofacial abnormalies in humans and the other organisms are common birth defects, although few are heritable conditions. Most research on basic body and facial structural development is interpreted from lower organisms, such as Drosophilia and zebrafish. Unlike the mouse, cats are strongly selected for facial structures. Felines are more related evolutionarily to humans than to mice, with similar genomic organization. Thus, transferring basic and clinical research on the processes that affect normal and abnormal development of craniofacial structures in the cat to humans will be extremely efficient. The long-term goal of this research is to understand the genetic components of craniofacial development in humans. The primary goal is to develop the feline into a model for human facial development. Burmese cats have a single gene defect that causes duplication of the upper maxillary region of the face. The interactions of mutations and genes for feline facial development will be more similar to humans than other current animal models. Three approaches will be used to develop the model. Specific Aim 1: Isolate feline homologs of developmental genes and gene-associated microsatellites from the cat BAC library. Genes in the HOX clusters and Sonic Hedgehog have been shown to strongly influence facial development. The hypothesis is that one of these genes causes the feline facial defect. Highly polymorphic microsatellite markers that are in juxtaposition to the genes will also be isolated from the cat. Specific Aim 2: Scan Sonic Hedgehog for causative mutations. Sonic hedgehog has a strong influence on the upper maxillary region. Specific Aim 3: Linkage analysis in feline pedigrees. Gene-associated markers will be analyzed in previously collected feline families that segregate for the cranial facial defect. This approach will support the candidate gene efforts. The hypothesis is that a linkage analysis will identify the chromosomal region for the candidate gene, focusing the search for the candidate gene. Once identified, mutation analyses of these genes in the cat or other species will lead to understanding the genetics of facial development in humans.