Tippy a novel mouse model for human ataxia epilepsy

描述(由申请人提供)：自发的和ENU诱导的小鼠突变对于它们模拟人类疾病的能力来说是一个非常宝贵的资源。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能够将新的表型与致病基因联系起来。然而，尽管它们意义重大，但许多小鼠突变还没有得到足够的表型特征来引发适当的科学兴趣。此外，许多研究人员不愿将资源投入到所需的位置克隆工作中，以确定致病分子损伤。因此，许多现有的小鼠突变资源没有得到充分利用，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。一个这样的突变体是自发的神经性小鼠突变体tippy。这种令人兴奋的突变于1977年在杰克逊实验室出现，但自1995年首次报告以来，无论是表型还是基因型，基本上都没有特征。纯合的Tippy突变体表现出共济失调和癫痫，并且无法在断奶年龄后存活。先天性共济失调和癫痫是常见的人类儿科神经系统疾病，通常是并存的，其发育和发病机制尚不清楚。我们已经确定Tippy小鼠具有两种非常有趣的神经表型，这两种表型引起了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状异常，这可能是Tippy突变型共济失调的基础。此外，我们还鉴定了这些突变体中可能导致癫痫的复杂的海马区畸形。这种畸形类似于在人类颞叶癫痫中常见的海马区发育不良，这是一种以前没有在小鼠身上建模的表型。因此，我们已经证明了Tippy突变体的小脑和海马区表型引起了基础和临床神经科学家的广泛兴趣。在这项建议中，我们提供电生理和免疫组织化学实验，以更全面地确定观察到的倾斜突变形态中枢神经系统异常的细胞和功能基础。我们还建议确定tippy突变体的潜在分子遗传损伤，我们已经将其定位于小鼠9号染色体远端的一个小的临界区，以将tippy基因与临床上重要的tippy神经表型联系起来。总而言之，这些实验将提供对Tippy突变的全面表征，这将为共济失调和癫痫的基本神经生物学提供新的见解。这些实验还将显著提高Tippy突变小鼠的价值和可及性，以便其他人可以更容易地利用这一宝贵的小鼠试剂。公共卫生相关性：这项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障碍有关。对导致潜在小脑和海马区畸形的发育机制的更好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.