Identification of mutation causing Purkinje cell degeneration in the shaker rat

引起摇床大鼠浦肯野细胞变性的突变的鉴定

• 批准号: 8512375
• 负责人: Stefan M. PULST
• 金额: $ 22.38万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512375
• 关键词: Abnormal coordination; Affect; Alleles; Animal Model; Animals; Anterior; Ataxia; Behavioral; Biochemical; Bioinformatics; Biological Models; Birth; Cancer Center; Candidate Disease Gene; Cells; Cerebellum; Cessation of life; Chromosome Mapping; Clinical; Collaborations; Core Facility; Custom; Devices; Disease; Exhibits; Exons; Explosion; Female; Functional disorder; Gait; Gene Expression; Genes; Genetic Markers; Goals; Grant; Haplotypes; Hereditary Disease; Human; Hybrids; Inbred WF Rats; Inherited; Inherited Spinocerebellar Degenerations; Laboratories; Link; Lobe; Location; Maps; Messenger RNA; Methods; Microsatellite Repeats; Modeling; Molecular; Motor; Movement; Multiple Sclerosis; Mus; Mutation; Phenotype; Prevalence; Proteins; Purkinje Cells; RNA Sequence Analysis; RNA Sequences; RNA Splicing; Rat Strains; Rattus; Rattus norvegicus; Rodent Model; Sequence Analysis; Sib Matings; Site; Testing; Transcript; Universities; Utah; Validation; Variant; X Chromosome; base; disability; endophenotype; fly; gene function; genetic variant; genome sequencing; interest; loss of function mutation; male; mutant; nervous system disorder; neuron loss; novel; postnatal; public health relevance; segregation; transmission process; treatment strategy

DESCRIPTION (provided by applicant): Degenerative ataxias are a group of neurological disorder associated with dysfunction of cerebellum and its connection. The clinical manifestations include progressive incoordination of movements and gait leading to complete disability and eventually to death. In humans, the prevalence of hereditary ataxias range from 6 to 20 cases for every 100,000 which is comparable to the prevalence of ALS or multiple sclerosis in the US. Rodent models of human ataxias have been limited to mice. The Shaker rat is a naturally occurring X- linked model for Purkinje cell degeneration in the Wistar Furth (WF) background. In contrast to most rodent models of human ataxias in which neuronal loss is not pronounced, the shaker rat progresses from a normal number of Purkinje cells at birth to almost complete loss at 1 year. Three specific aims are proposed: We will fine-map the shaker locus using F2's from an intercross of WF shaker rates with wildtype Brown Norway rats. A panel of 44 genetic markers that distinguish WF and BN alleles, informative in this cross, has been established. A second aim will identify the shaker mutation by RNA sequencing of shaker and wildtype RNAs isolated from pre-symptomatic and symptomatic cerebella. The third aim will employ whole genome sequencing for the case that the shaker mutation does not cause reduced abundance of the shaker transcript or is intronic. The overall goal of this proposal is the identification of the first gene in the rat leading to cerebellar PC degeneration and the establishment of the rat as a model system in which to test novel treatment strategies.

描述（由申请人提供）：退行性共济失调是一组与小脑及其连接功能障碍相关的神经系统疾病。 临床表现包括进行性运动和步态不协调，导致完全残疾，最终死亡。 在人类中，遗传性共济失调的患病率范围为每100，000例6至20例，与美国ALS或多发性硬化症的患病率相当。 人类共济失调的啮齿动物模型仅限于小鼠。 Shaker大鼠是Wistar Furth（WF）背景下自然发生的浦肯野细胞变性的X连锁模型。 与大多数人类共济失调的啮齿动物模型（其中神经元损失不明显）相反，摇动鼠从出生时正常数量的浦肯野细胞进展到1年时几乎完全丧失。 提出了三个具体的目标：我们将精细映射的摇床轨迹使用F2的WF摇床率与野生型布朗挪威大鼠的杂交。一个小组的44个遗传标记，区分WF和BN等位基因，信息在这个交叉，已经建立。 第二个目标是通过对从症状前和症状性小脑分离的shaker和野生型RNA进行RNA测序来鉴定shaker突变。 第三个目标将采用全基因组测序，用于shaker突变不引起shaker转录物丰度降低或为内含子的情况。 该提案的总体目标是鉴定大鼠中导致小脑PC变性的第一个基因，并建立大鼠作为测试新治疗策略的模型系统。