A gene-targeted mouse model for chorea-acanthocytosis
A gene-targeted mouse model for chorea-acanthocytosis
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DOI：
10.1111/j.1471-4159.2004.02924.x
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发表时间：
2005-02-01
影响因子：
4.7
通讯作者：
Sano, A
中科院分区：
文献类型：
--
作者：
Tomemori, Y;Ichiba, M;Sano, A
舞蹈病棘红细胞增多症是一种常染色体隐性遗传的神经退行性疾病，在脑病理学中有报道其纹状体的选择性变性。临床上，CHAC表现为亨廷顿病样神经精神症状和红细胞棘红细胞增多。最近，我们确定了基因，CHAC，编码一种新的蛋白质，chorein，其中一个缺失突变被发现在日本家庭与CHAC。在本研究中，我们已经确定了小鼠CHAC的cDNA序列和外显子-内含子结构的基因，并通过基因打靶技术产生了CHAC模型小鼠引入对应于人类疾病突变的第60-61外显子缺失。小鼠在老年时开始表现出棘红细胞增多和运动障碍。在行为学观察中，模型小鼠的自发活动显著减少，社会交往试验中的接触时间显著减少。脑组织病理学观察发现，突变小鼠纹状体内可见大量凋亡细胞。在神经化学测定中，多巴胺代谢产物高香草酸的浓度在包括突变小鼠中脑的部分中显著降低。这些发现与其他地方报道的人类结果一致，表明CHAC模型小鼠表现出轻度表型，成年后发病。因此，CHAC模型小鼠为研究人类疾病提供了良好的模型系统。
Chorea-acanthocytosis (CHAC) is a hereditary neurodegenerative disorder with autosomal recessive transmission, in which selective degeneration of striatum has been reported in brain pathology. Clinically, CHAC shows Huntington's disease-like neuropsychiatric symptoms and red blood cell acanthocytosis. Recently, we identified the gene, CHAC, encoding a novel protein, chorein, in which a deletion mutation was found in Japanese families with CHAC. In the present study, we have identified the mouse CHAC cDNA sequence and the exon-intron structures of the gene and produced a CHAC model mouse introducing no. 60-61 exon deletion corresponding to a human disease mutation by a gene-targeting technique. The mice began to show acanthocytosis and motor disturbance in old age. In behavioral observations, locomotor activity was significantly decreased and the contact time at social interaction test was decreased significantly in the model mice. In the brain pathology, many apoptotic cells were observed in the striatum of the mutant mice. In neurochemical determinations, the dopamine metabolite, homovanillic acid, concentration decreased significantly in the portion including the midbrain of the mutant mice. These findings are consistent with the human results reported elsewhere and indicate that the CHAC model mice showed a mild phenotype with late adult onset. The CHAC model mouse therefore provides a good model system to study the human disease.