Characterization of a Novel Ataxia Phenotype

项目摘要/摘要 定义神经肌肉表型的遗传变异有助于深入了解 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疾病的遗传机制。这些发现是 通过经典的遗传学方法确定表型特征，然后定义 这就是那个缺陷的原因。这种方法对一系列发现起到了重要作用，从而产生了更多 彻底了解疾病的潜在机制。根据这项建议提出的项目如下 一种类似的方法。我们试图确定并表征一种可能导致严重、 “新奇共济失调表型”(NAP)在我们实验室被发现，最终目的是揭示小说 共济失调的潜在机制。这项建议概述了实验以确定受影响的组织类型和 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 来进行实验验证。这种方法确保进展不完全依赖于特定的结果， 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将提供遗传图谱，从而阐明潜在的非编码变体，这些变体可能 诱导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小鼠的转录差异以提供潜在的机制 表型。通过计算分析和实验，成功地识别了变种 验证将允许进一步的实验，以更好地理解变体的作用机制，如 在目标中概述。鉴于共济失调的表型，我们怀疑初级组织受到影响。 将是小脑和/或脑干，通过繁殖，我们已经确定这种变异是遗传的 常染色体隐性遗传模式。通过初步的基因组分析，我们鉴定出了几个新的 并排除了几个与共济失调表型有关的已知基因。这个项目的成果 有望进一步深入了解共济失调的分子机制，并有可能 作为改善共济失调症状的治疗发展的典范。这个项目是设计的 扩大首席调查员的技能和培训，目标是全面培训 生物信息学和小鼠模型的表征。

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.