Molecular Analysis of a Canine CNS Developmental Defect

描述（由申请人提供）：许多人类中枢神经系统（CNS）发育障碍具有重要的遗传成分，但潜在的遗传缺陷通常是未知的。这类疾病可分为两类：一类是罕见的常染色体隐性遗传病，家族物质不足或遗传异质性使连锁分析难以进行；另一类是较为常见的遗传疾病，但遗传模式复杂。大多数这类疾病没有在实验室小鼠群体中自发发生，并且缺乏致病基因或基因的身份，因此不可能通过靶向基因破坏来创建小鼠敲除模型。然而，狗是人类遗传疾病的准确和自然发生的动物模型的丰富来源，可用于发现潜在的遗传原因。最近，我们观察到一个大型犬家系，其中胎儿脑和脊髓发育骤停作为一种简单的常染色体隐性性状发生，并产生一种致命的临床表型，与人类桥小脑发育不全I型（PCH I）非常相似。PCH I是一种发育中的中枢神经系统的神经退行性疾病，影响脑干、小脑和脊髓的运动神经元，但这种疾病的表型表达各不相同，甚至在家族中也是如此。这种异质性和用于连锁分析和定位克隆的PCH I家系的缺乏使得难以确定该疾病的遗传基础。我们建议采取遗传方法鉴定负责这种犬的遗传中枢神经系统发育障碍模型的基因。这种方法现在是可行的，利用最近可用的犬科动物连锁和辐射杂交图谱以及其他新的高分辨率遗传资源来比较候选位置克隆疾病基因。该项目的目的是使用连锁分析，结合详细描述犬疾病的进展和病理，以确定潜在的基因缺陷。除了确定神经发育异常背后的主要缺陷外，这些研究将提高对异质人类疾病共同发病机制的理解，并为开发此类儿科疾病的潜在治疗方法提供一个具有良好特征的大型动物模型。

DESCRIPTION (provided by applicant): Many human disorders of central nervous system (CNS) development have an important genetic component, but the underlying genetic defects are often unknown. Such disorders fall into two groups: 1) rare autosomal recessive disorders with insufficient family material or with genetic heterogeneity that confounds linkage analysis, and 2) more common genetic disorders but which have complex patterns of inheritance. Most such disorders have not been observed occurring spontaneously in laboratory mouse populations, and lacking the identity of the causative gene or genes, it is not possible to create mouse knockout models by targeted gene disruption. However, dogs are a rich source of accurate and naturally occurring animal models of human genetic disease that can be used for the discovery of underlying genetic causes. Recently, we have observed a large pedigree of dogs in which fetal arrest of brain and spinal cord development occurs as a simple autosomal recessive trait and produces a lethal clinical phenotype that closely models pontocerebellar hypoplasia type I (PCH I) of humans. PCH I is a neurodegenerative disorder of the developing central nervous system affecting the brainstem, cerebellum, and motor neurons of the spinal cord, but phenotypic expression of the disease varies, even within families. This heterogeneity and a paucity of PCH I pedigrees for use in linkage analysis and positional cloning make it difficult to determine the genetic basis of the disorder. We propose to take a genetic approach for the identification of the gene responsible for this canine model of an inherited CNS developmental disorder. This approach is now feasible using recently available canine linkage and radiation hybrid maps and other new high-resolution genetic resources for comparative positional-candidate cloning of disease genes. The aims of this project are to use linkage analysis, combined with detailed description of the progression and pathology of the canine disorder, to determine the underlying gene defect. In addition to identifying the primary defect that underlies the neurodevelopmental abnormality, these studies will improve understanding of a pathogenesis that is common to a heterogeneous group of human disorders and provide a well-characterized large animal model for potential development of treatments for pediatric disorders of this type.