Characterization of a Novel Ataxia Phenotype

项目总结/摘要 定义负责神经肌肉表型的遗传变异， 神经机制以及对人类疾病机制的洞察。小鼠模型也被 用于了解导致相关神经系统疾病的遗传机制。这些发现是 通过经典的遗传学方法来描述表型，然后定义基因型， 解释了这个缺陷这种方法对许多发现都很有帮助， 深入了解疾病的潜在机制。根据这项建议提出的项目如下： 类似的方法。我们试图确定和表征一种潜在的新变异， 我们实验室发现的"新型共济失调表型"（novelataxiaphenotype，nap）的最终目标是阐明 共济失调的潜在机制该提案概述了表征受影响组织类型的实验， 评估全基因组测序（WGS）和RNA测序，以分离潜在的致病遗传变异 进行实验验证。这一办法确保进展不完全取决于具体结果， 相反，可以同时进行几个实验，这将增加成功的可能性。我们的方法 利用WGS将提供遗传景观，从而阐明潜在的非编码变异， 诱发nap小鼠的表型。在确定哪种组织类型受到影响后，我们将进行RNA 测序以阐明nap小鼠中的转录组差异，以提供潜在的机制 表型通过计算分析和实验成功地识别了变体 验证将允许进一步的实验以更好地理解变体的作用机制， 在目标中概述。鉴于共济失调表型的表现，我们怀疑受累的原发组织 将是小脑和/或脑干，通过育种，我们已经确定，这种变异是遗传的， 常染色体隐性遗传通过初步的基因组分析，我们已经确定了几个新的 候选人，并排除了几个已知的基因负责共济失调表型。该项目的结果 有望为共济失调的分子机制提供进一步的见解， 作为改善共济失调病理学的治疗开发模型。这个项目是为了 扩大主要调查员的技能和培训，目标是在以下方面进行全面培训： 小鼠模型的生物信息学和表征。

PROJECT SUMMARY/ABSTRACT Defining genetic variation responsible for neuromuscular phenotypes has provide insight about basic neurological mechanisms as well as insight on human disease mechanisms. Mouse models have also been used to understand genetic mechanisms that cause relevant neurological conditions. These discoveries were made through the classic genetic approach of characterizing a phenotype and then defining the genotype that accounts for that defect. This approach has been instrumental for a host of discoveries resulting in a more thorough understanding of underlying mechanisms of disease. The project put forth under this proposal follows a similar approach. We seek to identify and characterize a potentially novel variant responsible for a severe, “novel ataxia phenotype” (nap) discovered in our lab with the ultimate goal of shedding light on novel mechanisms underlying ataxia. This proposal outlines experiments to characterize the affected tissue type and evaluate whole genome sequencing (WGS) and RNA sequencing to isolate potentially causal genetic variants to experimentally validate. This approach ensures that progress is not wholly dependent on a specific result, rather several experiments can be done in concert that will increase the probability of success. Our approach of utilizing WGS will providing the genetic landscape thereby elucidating potential noncoding variants that may elicit the phenotype in the nap mice. After determining which tissue type is affected, we will perform RNA sequencing to elucidate transcriptomic differences in the nap mice to provide potential mechanisms underlying the phenotype. Successfully identifying the variant through computationally analysis and experimental validation will allow for further experiments to better understand the mechanism of action of the variant, as outlined in the aims. Given the presentation of the ataxia phenotype, we suspect the primary tissue affected will be the cerebellum and/or brainstem and through breeding, we have established that this variant is inherited in an autosomal recessive pattern. Through preliminary genome analysis, we have identified several novel candidates and excluded several known genes responsible for ataxia phenotypes. The results of this project are expected to provide further insight into the molecular mechanisms that underlie ataxia and will potentially serve as a model for therapeutic development to ameliorate ataxia symptomology. This project was designed to expand the skills and training of the principal investigator with the goal of comprehensive training in bioinformatics and characterization of the mouse model.