Identification of the gene for hereditary spinocerebellar degeneration and its usage for diagnosis.

遗传性脊髓小脑变性基因的鉴定及其诊断用途。

• 批准号: 09557020
• 负责人: YOSHIKI Takashi
• 金额: $ 3.9万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09557020/
• 关键词: spinocerebellar degeneration; CAG triplet repeat; CACNL1A4; CACNLIA4; ポリグルタミン鎖; CAG反復配列; 遺伝子診断

The dominantly inherited spinocerebellar ataxias are a cluster of genetically heterogeneous neuro-degenerative disorders. More than 500 people living in Hokkaido are affected with these diseases. Recent advances in molecular genetics have led to the identification of 7 loci named as SCAl to SCA7.Among them, abnormal expansions of the CAG trinucleotide repeat have been identified in the patients with SCAl, SCA2 and SCA3. Although number of patients exceeds 30 % in Japanese ataxic patients, the location and specific abnormalities of the gene for Holmes' ataxia were unknown when we started this research. Through two years research, we have clarified following evidences ;1) The responsible gene for the half of the patients with Holiness' ataxia in the Japanese are identical to that of SCA6.2) The responsible gene for SCA6 is a gene for alphalA - voltage dependent calcium channel (CACNL1A4) mapped at 19p13.3) An abnormal expansions of the CAG trinucleotide repeat located in the CACNL1A4 was observed in the patients with SCA6.4) The number of CAG repeat inversely correlated with age of onset.5) Strong linkage disequilibrium suggested that SCA6 in the Japanese in Hokkaido may derive from a single common ancestry.It should be solved in a future that why and how expanded CAG repeat, which translated into poly glutamine chain, causes a selective neuronal cell death.

显性遗传性脊髓小脑共济失调是一组遗传异质性神经退行性疾病。居住在北海道的 500 多人受到这些疾病的影响。分子遗传学的最新进展导致鉴定出7个基因座，命名为SCA1至SCA7。其中，在SCA1、SCA2和SCA3患者中已鉴定出CAG三核苷酸重复的异常扩增。尽管日本共济失调患者的患者数量超过30%，但当我们开始这项研究时，霍姆斯共济失调基因的位置和具体异常情况尚不清楚。经过两年的研究，我们澄清了以下证据：1）日本一半的Holies共济失调患者的致病基因与SCA6相同。2）SCA6的致病基因是α1A-电压基因依赖钙通道 (CACNL1A4) 定位于 19p13.3) 在患有以下疾病的患者中观察到位于 CACNL1A4 的 CAG 三核苷酸重复序列的异常扩增SCA6.4) CAG重复次数与发病年龄呈负相关。5)强连锁不平衡表明北海道日本人的SCA6可能源自单一共同祖先。CAG为何以及如何扩展是未来需要解决的问题重复，翻译成聚谷氨酰胺链，导致选择性神经元细胞死亡。

项目成果

Yoshiki, T.: Pathological point of view for Collagen disease.Hokkaido Med.J., 3-6 (1997)

Yoshiki, T.：胶原病的病理学观点。北海道医学杂志，3-6 (1997)

Yoshiki, T.: "Animal model for HAM/TSP" NITIDOKUIHO. 43. 232-241 (1998)

Yoshiki, T.：“HAM/TSP 动物模型”NITIDOKUIHO。

佐々木秀直: "最新内科学体系68" 中山書店, 229-235 (1997)

佐佐木秀直：《最新内科系统68》中山书店，229-235（1997）

Yabe, I., et.al.: "SCA6 mutation analysis in a large cohort of the Japanese patients with late-onset pure cerebellar ataxia." J.Neuro.Sci.156. 89-95 (1998)

Yabe, I., et.al.：“对一大群日本迟发性纯小脑性共济失调患者进行 SCA6 突变分析。”

Takiyama,Y.: "Meternal anticipation in Machado-Joseph disease(MJD): some maternal factors independent of the number of CAG repeat units may play a role in genetic anticipation in a Japanese MJD family." J.Neuro.Sci.,. 155. 141-145 (1998)

Takiyama, Y.：“马查多-约瑟夫病 (MJD) 的母亲预期：一些与 CAG 重复单位数量无关的母亲因素可能在日本 MJD 家族的遗传预期中发挥作用。”