Molecular Analysis of a Canine CNS Developmental Defect

描述(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。这些疾病分为两组：1)罕见的常染色体隐性遗传病，具有家庭材料不足或遗传异质性，混淆了连锁分析；2)更常见的遗传疾病，但具有复杂的遗传模式。大多数这样的疾病还没有在实验室小鼠群体中自发发生，并且缺乏一个或多个致病基因的一致性，因此不可能通过靶向基因破坏来创建小鼠基因敲除模型。然而，狗是人类遗传病的准确和自然发生的动物模型的丰富来源，可以用于发现潜在的遗传原因。最近，我们观察到了一大批狗的家系，其中脑和脊髓发育的胎儿停滞是一种简单的常染色体隐性遗传性状，并产生了一种致命性的临床表型，与人类的桥小脑发育不全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，但该疾病的表型表达不同，即使在家族内也是如此。这种异质性和用于连锁分析和位置克隆的PCH I家系的稀少，使得确定该疾病的遗传基础变得困难。我们建议采用遗传学的方法来鉴定导致这种遗传性中枢神经系统发育障碍的犬模型的基因。这种方法现在是可行的，使用最近可用的犬类连锁和辐射杂交图谱和其他新的高分辨率遗传资源来比较位置候选克隆疾病基因。这个项目的目的是使用连锁分析，结合对犬病进展和病理的详细描述，来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，这些研究还将提高对一组不同人类疾病常见发病机制的理解，并为这类儿科疾病的潜在治疗开发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.