A Mouse Model for a Dominant, Adult-Onset Ataxia (pilot)

我们已经在CSU小鼠群体中发现了一种表型异常，该表型异常表现为成年发病， 进行性共济失调对这种变异株（BxR23）的育种分析表明， 这种共济失调是以常染色体显性方式传递的孟德尔性状。严重程度的差异 然而，纯合子和杂合子之间的表型表明，该性状是不完全的 占主导地位。我们假设，负责这一特征的突变存在于一个尚未表征的 小鼠基因另一种假设是，突变存在于一个小鼠基因中， 以前的特点。我们正试图通过同时映射这些替代方案， 通过连锁分析和开发突变检测试验， 几个候选小鼠基因。受影响的BxR23小鼠的尸检未能确定明确的 共济失调表型的生理基础，因此遗传方法显然是表征 这种混乱。我们还建议进一步记录共济失调的发作和进展，通过标准的 观察方法，如旋转杆测试和步幅测量。这样，一个量化的 可以获得纯合子和杂合子之间表型差异的量度。虽然 有几十种人类共济失调综合征是由常染色体显性突变引起的，目前还没有已知的 显性共济失调的小鼠模型。BxR23小鼠可能被证明是一个有用的模型，用于研究 成人发作的进行性共济失调的发展。 神经退行性疾病对老龄化人口造成巨大损失。许多这些疾病 是以常染色体显性遗传的方式遗传的这些疾病的小鼠模型，如BxR23小鼠 菌株，是了解人类神经退行性疾病的分子和生物化学基础的有价值的工具 紊乱

We have identified a phenotypic deviant within our CSU mouse colony that shows an adult-onset, progressive ataxia. Breeding analysis of this deviant strain (BxR23) suggests that the underlying cause of this ataxia is a Mendelian trait, transmitted in an autosomal dominant manner. Differences in severity of the phenotype between homozygotes and heterozygotes, however, suggest that the trait is incompletely dominant. We hypothesize that the mutation responsible for this trait resides in an as yet uncharacterized mouse gene. An alternative hypothesis is>that the mutation resides in a mouse gene that has been previously characterized. We are attempting to distinguish these alternatives by simultaneously mapping the mutation within the mouse genome through linkage analysis and developing mutation-detection assays for several candidate mouse genes. Necropsies of affected BxR23 mice have failed to identify a clear physiological basis for the ataxic phenotype, so a genetic approach is clearly the best way to characterize this disorder. We also propose to further document the onset and progression of the ataxia through standard observation methods such as the rotarod test and stride length measurements. In this way, a quantitative measure of phenotypic difference between homozygotes and heterozygotes can be attained. Although there are dozens of human ataxia syndromes caused by autosomal dominant mutations, there are no known mouse models of dominant ataxias. The BxR23 mouse may prove to be a useful model for studying the development of adult-onset, progressive ataxias in humans. Neurodegenerative diseases exact an enormous toll on the aging human population. Many of these diseases are inherited in an autosomal dominant fashion. Mouse models for these diseases, like the BxR23 mouse strain, are valuable tools in understanding the molecular and biochemical basis of human neurodegenerative disorders.