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非常有价值的资源，因为它们有能力模拟人类疾病。这些突变体的研究为临床相关的基本生物学机制提供了新的见解，这在标准的基因靶向方法中是不明显的。这些突变体的关键价值是将新表型与致病基因型联系起来的能力。然而，尽管它们具有重要意义，许多小鼠突变体还没有充分的表型特征来激发适当的科学兴趣。此外，许多研究人员不愿投入资源进行所需的位置克隆工作，以确定致病的分子病变。因此，许多现存的小鼠突变体资源明显未得到充分利用，对科学界的价值有限，尽管已经投入了大量资源用于它们的产生和维护。其中一种突变是自发性神经系统小鼠突变体tippy。这种突变于1977年在杰克逊实验室出现，但自1995年首次报告以来，无论是表现型还是基因型，基本上都没有被描述出来。纯合子突变体表现出共济失调和癫痫，不能存活过断奶期。先天性共济失调和癫痫是常见的儿童神经系统疾病，通常是合并症，其发育和发病机制尚不清楚。我们已经确定，小老鼠有两种非常有趣的神经表型，这是基础和临床神经科学家广泛感兴趣的。我们的初步分析揭示了新的小脑浦肯野细胞树突状异常，可能是小脑突变体共济失调的基础。此外，我们还描述了这些突变体中复杂的海马畸形可能导致癫痫。这种畸形类似于人类颞叶癫痫中常见的海马发育不良，这种表型以前没有在小鼠中建模。因此，我们已经证明tippy突变体的小脑和海马表型引起了基础和临床神经科学家的广泛兴趣。在这一建议中，我们提出电生理和免疫组织化学实验来更完整地定义观察到的tipppy突变CNS形态学异常的细胞和功能基础。我们还建议鉴定tippy突变体中潜在的分子遗传病变，我们已经定位在小鼠远端9号染色体的一个小关键区域，将tippy基因型与临床上重要的tippy神经表型联系起来。总之，这些实验将提供一个全面的突变特征，这将为共济失调和癫痫的基本神经生物学提供新的见解。这些实验也将显著提高tipppy突变小鼠的价值和可及性，从而使其他人更容易利用这种有价值的小鼠试剂。公共卫生相关性：本提案的重点是确定先天性共济失调和癫痫的病因。这是两种共病性神经发育障碍，通常与毁灭性的认知和运动缺陷有关。提高对导致潜在小脑和海马畸形的发育机制的理解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.