Molecular genetical approach for multifactorial neuropsychiatric diseases

多因素神经精神疾病的分子遗传学方法

• 批准号: 16390326
• 负责人: SANO Akira
• 金额: $ 7.49万
• 依托单位: Kagoshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390326/
• 关键词: Chorea-acanthocytosis; CHAC (VPS13A); model mouse; phenotype; C57BL; 6J; BALB; cbyJ; DBA; 2J; modifying genes; 神経変性; 個体差; 多因子; modifier遺伝子; 運動障害; 有棘赤血球症; CHAC

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.

棘细胞舞蹈症是一种常染色体隐性遗传的人类遗传性神经退行性疾病，在脑病理学中已有选择性纹状体变性的报道。在临床上，Chac表现出亨廷顿病样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可以观察到症状的很大变化。最近，我们发现了一个编码Chorein蛋白的基因Chac(VPS13A)，在日本Chac家族中发现了一个缺失突变。然后，我们鉴定了小鼠Chac基因序列和该基因的外显子-内含子结构，并通过基因打靶技术获得了相应于人类疾病突变的引入#60-61外显子缺失的Chac模型小鼠。这些小鼠在变老后开始出现棘细胞增多和运动障碍。在行为学观察中，模型组小鼠的运动活动明显减少，社会交往测试中的接触时间显著减少。在脑组织病理学中，突变小鼠的纹状体内可见大量的凋亡细胞。在神经化学检测中，突变小鼠包括中脑在内的部分多巴胺代谢物、HVA浓度显著降低。这些发现与其他地方报道的人类结果很好地一致，并表明CHAC模型小鼠表现出轻微的表型，成年发病较晚。因此，Chac模型小鼠为研究人类疾病提供了一个很好的模型系统。这些小鼠是129和C57BI/B6的杂交种，在纹状体和其他表型的退变程度上有很大的差异，这可能表明存在修饰基因。然后用C57BL/6J、BALB/cbyJ和DBA/2J三种品系建立CHAc模型小鼠。只有DBA/2J Chac模型小鼠从出生后3个月开始体重下降。

项目成果

精神神経疾患の遺伝学-臨床遺伝学から分子遺伝学

神经精神疾病的遗传学 - 从临床遗传学到分子遗传学

• 发表时间: 2004
• 期刊: 精神神経学雑誌 106
• 作者: Y.Tomemori;et al.;佐野輝;佐野輝;佐野輝
• 通讯作者: 佐野輝

分子精神医学

分子精神病学

• 发表时间: 2008
• 作者: 前川素子;大隅典子
• 通讯作者: 大隅典子

精神疾患の遺伝子研究

精神障碍的遗传学研究

• 发表时间: 2005
• 期刊: 精神医学 47・4
• 作者: 中村雅之;佐野輝
• 通讯作者: 佐野輝

Changes in expression of prosaposin in the rat facial nerve nucleus after facial nerve transection

• DOI: 10.1016/j.neures.2005.03.009
• 发表时间: 2005-07
• 期刊: Neuroscience Research
• 影响因子: 2.9
• 作者: Kana Unuma;Jie Chen;S. Saito;N. Kobayashi;Kohji Sato;Kyoko Saito;H. Wakisaka;K. Mominoki;A. Sano;S. Matsuda

セロトニントランスポーター

血清素转运蛋白

• 发表时间: 2005
• 期刊: 分子精神医学 5・2
• 作者: 中村雅之;佐野輝
• 通讯作者: 佐野輝