Tippy a novel mouse model for human ataxia epilepsy

描述（由申请人提供）：自发和ENU诱导的小鼠突变体是一种非常宝贵的资源，因为它们能够模拟人类疾病。对这些突变体的研究为基本的临床相关生物学机制提供了新的见解，这些机制通过标准的基因靶向方法是不明显的。这些突变体的关键价值在于将新的表型与致病基因型相关联的能力。然而，尽管它们的重要性，许多小鼠突变体还没有足够的表型特征，以激发适当的科学兴趣。此外，许多研究人员不愿意将资源投入到所需的定位克隆工作中，以确定致病分子病变。因此，许多现存的小鼠突变体资源被显著地利用不足，并且对科学界的价值有限，尽管已经投入了大量的资源用于它们的产生和维持。其中一个突变体是自发神经性小鼠突变体tippy。这种尖端突变于1977年在杰克逊实验室出现，但自1995年首次报道以来，无论是表型还是基因型，基本上都没有得到表征。纯合子tippy突变体表现出共济失调和癫痫，不能存活过断奶年龄。先天性共济失调和癫痫是常见的人类儿科神经系统疾病，通常是共病，其发展和发病机制知之甚少。我们已经确定，tippy小鼠有两个非常有趣的神经表型，这是基础和临床神经科学家的广泛兴趣。我们的初步分析揭示了新的小脑浦肯野细胞树突异常，可能是共济失调的tippy突变体的基础。此外，我们的特点是复杂的海马畸形在这些突变体可能导致癫痫。这种畸形与人类颞叶癫痫中常见的海马发育不良相似，这是一种先前未在小鼠中建模的表型。因此，我们已经证明，小脑和海马表型的tippy突变体的基础和临床神经科学家的广泛兴趣。在这个建议中，我们提出了电生理和免疫组化实验，以更完整地定义所观察到的tippy突变体形态学CNS异常的细胞和功能基础。我们还建议确定潜在的分子遗传病变的tippy突变体，我们已经定位到一个小的关键区域远端小鼠9号染色体，与临床重要的tippy神经系统表型的tippy基因型。总之，这些实验将提供一个全面的特点的tippy突变，这将提供新的见解共济失调和癫痫的基础神经生物学。这些实验还将显著提高tippy突变小鼠的价值和可获得性，以便其他人可以更容易地利用这种有价值的小鼠试剂。公共卫生相关性：该提案的重点是定义先天性共济失调和癫痫的病因。这是两种共病的神经发育障碍，通常与毁灭性的认知和运动缺陷有关。进一步了解导致小脑和海马畸形的发育机制将提供有价值的诊断和预后信息，并影响治疗。

DESCRIPTION (provided by applicant): Spontaneous and ENU-induced mouse mutants are a tremendously valuable resource for their ability to model human disease. The study of these mutants has provided new insights into basic clinically relevant biological mechanisms, which would not have been apparent through standard gene-targeting approaches. The key value of these mutants is the ability to associate novel phenotypes with the causative genotype. However, despite their significance, many mouse mutants have not been sufficiently phenotypically characterized to spark appropriate scientific interest. Further, many investigators are hesitant to invest resources into the required positional cloning efforts to identify the causative molecular lesions. As a result, many extant mouse mutant resources are significantly underutilized and of limited to value to the scientific community, despite the already significant resources invested into their generation and maintenance. One such mutant is the spontaneous neurological mouse mutant tippy. The tippy mutation arose at Jackson Labs in 1977 but has remained essentially uncharacterized, both phenotypically and genotypically since its first report in 1995. Homozygous tippy mutants exhibit ataxia and epilepsy and do not survive past weaning ages. Congenital ataxia and epilepsy are common human pediatric neurological disorders that are often co-morbid, and their developmental and pathogenesis poorly understood. We have determined that tippy mice have two very interesting neurological phenotypes, which are of broad interest to both basic and clinical neuroscientists. Our preliminary analysis has revealed novel cerebellar Purkinje cell dendritic abnormalities that likely underlie the ataxia in tippy mutants. Further, we have characterized a complex hippocampal malformation in these mutants likely causative for epilepsy. This malformation is similar to hippocampal dysplasias commonly observed in human temporal lobe epilepsy, a phenotype which has not been previously modeled in mice. Thus, we have demonstrated that the cerebellar and hippocampal phenotypes of tippy mutants are of broad interest to both basic and clinical neuroscientists. In this proposal, we present electrophysiological and immunohistochemical experiments to more completely define the cellular and functional basis of the observed tippy mutant morphological CNS abnormalities. We also propose to identify the underlying molecular genetic lesion in tippy mutants, which we have localized to a small critical region on distal mouse chromosome 9, to associate the tippy genotype with the clinically important tippy neurological phenotypes. Together these experiments will provide a comprehensive characterization of the tippy mutation which will provide new insights into the basic neurobiology of ataxia and epilepsy. These experiments will also significantly enhance the value and accessibility of tippy mutant mice, so that others may more readily exploit this valuable mouse reagent. PUBLIC HEALTH RELEVANCE: This proposal is focused on defining the etiology of congenital ataxia and epilepsy. These are two co-morbid neurodevelopmental disorders that are often associated with devastating cognitive and motor deficits. An improved understanding of the developmental mechanisms leading to the underlying cerebellar and hippocampal malformations will provide valuable diagnostic and prognostic information and influence treatment.