Molecular genetical approach for multifactorial neuropsychiatric diseases

舞蹈病-棘细胞增多症（ChAc）是一种常染色体隐性遗传的人类遗传性神经退行性疾病，在脑病理学中有纹状体选择性变性的报道。临床上，ChAc表现为类似亨廷顿氏病的神经精神症状和红细胞棘细胞增多症，即使在兄弟病例中也观察到症状的很大变化。最近，我们在日本CHAC家族中发现了一个缺失突变的基因，CHAC （VPS13A）编码一种名为chorein的蛋白质。然后，我们鉴定了小鼠CHAC cDNA序列和基因的外显子-内含子结构，并通过基因靶向技术构建了引入与人类疾病突变相对应的#60-61外显子缺失的CHAC模型小鼠。老年小鼠开始出现棘细胞增多症和运动障碍。在行为观察中，模型小鼠的运动活动明显减少，社交互动测试的接触时间明显减少。在脑病理学上，突变小鼠纹状体中可见大量凋亡细胞。在神经化学测定，多巴胺代谢物，HVA浓度在突变小鼠包括中脑部分显著下降。这些发现与其他地方报道的人类结果非常一致，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一个良好的模型系统。129与C57BI/B6杂交产生的小鼠，纹状体和其他表型的变性程度存在很大差异，可能存在修饰基因。然后用背景菌株C57BL/6J、BALB/cbyJ和DBA/2J制备chac模型小鼠。只有DBA/2J chac模型小鼠在出生后3个月出现体重下降。

Chorea-acanthocytosis (ChAc) is a human 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, and much variation in symptoms are observed even in brother cases. Recently, we identified the gene, CHAC (VPS13A) encoding a protein named chorein in which a deletion mutation was found in Japanese ChAc families. Then we identified the mouse CHAC cDNA sequence and the exon-intron structures of the gene, and produced a ChAc-model mouse introducing #60-61 exons-deletion corresponding to a human disease mutation by gene-targeting technique. The mice began to show acanthocytosis and motor disturbance after becoming 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 determination, dopamine-metabolite, HVA concentration decreased significantly in the portion including midbrain of the mutant mice. These findings are well consistent with the human results reported elsewhere and indicate that the ChAc-model mice showed mild phenotype with late adult onset. The ChAc-model mouse therefore provides a good model system to study the human disease. The mice are produced as hybrid of 129 and C57BI/B6, and there are much variations in the degree of degeneration in the sriatum and other phenotypes, which might suggest the existence of modifier genes. Then we produced the ChAc-model mouse with three kinds of strains-background, C57BL/6J, BALB/cbyJ, and DBA/2J. Only DBA/2J ChAc-model mice showed reduced body weight from 3 months after birth.