A broad phenotypic screen identifies novel dominant phenotypes in Huntington's disease CAG knock-in mice

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by abnormal voluntary and involuntary movements, cognitive impairment and psychiatric disturbances. In order to identify phenotypic changes in the mouse that are most likely to be relevant to events triggered by the CAG repeat expansion in HD patients, we are interested in the earliest events that are triggered by expression of a single allele's worth of full-length mutant huntingtin in the mouse, whether at the molecular, cellular or whole animal level. To this end, we have undertaken a broad-based, unbiased phenotypic screen in heterozygous HdhQ111/+ C57BL/6J mice. For expression profiling analysis, four male mice at the age of 18 weeks were analysed versus a pool of four male wildtype mice (reference) at the same age. For each single mouse, two chip hybridizations, including a dye-swap experiment, were performed per tissue. Using our genome-wide microarray platform, we performed transcriptome analysis of liver and brain.亨廷顿舞蹈症（Huntington's disease, HD）是一种常染色体显性遗传的神经退行性疾病，以异常的自主运动与非自主运动、认知障碍及精神紊乱为核心临床特征。为了识别与亨廷顿患者体内CAG重复扩增（CAG repeat expansion）触发的病理事件最具相关性的小鼠表型变化，本研究聚焦于小鼠体内单等位基因剂量的全长突变亨廷顿蛋白表达所引发的最早事件——无论该事件发生于分子、细胞还是整体动物层面。为此，我们在杂合型HdhQ111/+ C57BL/6J小鼠中开展了一项广谱、无偏倚的表型筛选。针对表达谱分析环节，我们选取了4只18周龄的雄性受试小鼠，并以同年龄段的4只雄性野生型小鼠的混合样本作为对照参照。对于每一只受试小鼠，我们针对每种组织完成了两次芯片杂交实验，其中包含一次染料互换（dye-swap）实验。依托全基因组微阵列（genome-wide microarray）平台，我们对肝脏与脑组织开展了转录组分析。