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

我们已经在我们的CSU小鼠群体中发现了一个表型异常，显示出成体发病， 进行性共济失调。对该变异株(BxR23)的育种分析表明，其潜在原因是 这种共济失调是孟德尔人的特征，以常染色体显性方式传播。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，导致这种特征的突变存在于一种尚未确定特征的 老鼠基因。另一种假设是，突变存在于一种小鼠基因中，这种基因已经被 先前所描述的。我们正试图通过同时映射 通过连锁分析和建立突变检测方法检测小鼠基因组中的突变 几个候选的老鼠基因。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 这种紊乱。我们还建议通过以下标准进一步记录共济失调的发生和发展 观察方法，如转杆测试和步长测量。这样一来，一个量化的 可以测量纯合子和杂合子之间的表型差异。尽管在那里 是否有数十种人类共济失调综合征是由常染色体显性突变引起的，目前尚不清楚 显性共济失调小鼠模型。BxR23小鼠可能被证明是一个有用的模型来研究 成人起病，进行性共济失调在人类的发展。 神经退行性疾病对老龄化的人类人口造成了巨大的损失。这些疾病中的许多 以常染色体显性方式遗传。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变的分子和生化基础的宝贵工具 精神错乱。

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.