Mapping of the gene for Holmes' ataxia by searching of triplet repeats

通过搜索三联体重复序列绘制福尔摩斯共济失调基因图谱

• 批准号: 09470057
• 负责人: IKEDA Hitoshi
• 金额: $ 3.65万
• 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-09470057/
• 关键词: spinocerebellar degeneration; CAG triplet repeat; Holmes' ataxia; 遺伝性脊髄小脳変性症; Holmes失調症; CAG反復配列; ポリグルタミン鎖病

Holmes' ataxia is one of the most popular spinocerebellar ataxia in the Japanese. The number of patients exceeds 30 % among ataxic patients. Although recent advances in molecular genetics have revealed 7 different genes for spinocerebellar ataxia, named as SCAl to SCA7, the gene for Holmes' ataxia remains unknown. The purpose of this project is to identify the responsible gene for Holmes's ataxia by linkage analysis. Since weak genetic anticipation is observed in this disease, abnormal expansions of the CAG trunucleotide repeat is suggested as gene abnormality. At first we have made a comparison between Holmes' ataxia and known hereditary ataxia, then we have found followings ;1) The responsible gene for the half of the patients with Holmes's ataxia in the Japanese are identical to that of SCA6.2) The responsible gene for SCA6 is a gene for alpha lA - voltage dependent calcium channel (CACNLlA4) mapped at 19p13.3) An abnormal expansions of the CAG trunucleotide 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 dearth.

Holmes' ataxia是日本最常见的脊髓小脑性共济失调之一。在共济失调患者中，患者人数超过30%。尽管分子遗传学的最新进展已经揭示了7种不同的脊髓小脑共济失调基因，命名为SCA 1至SCA 7，但霍姆斯共济失调的基因仍然未知。本研究的目的是通过连锁分析确定Holmes共济失调的致病基因。由于在这种疾病中观察到弱遗传预期，CAG三核苷酸重复的异常扩增被认为是基因异常。首先将Holmes共济失调与已知的遗传性共济失调进行了比较，发现：1）日本Holmes共济失调患者中一半的致病基因与SCA 6相同。2）SCA 6的致病基因是α 1A-电压依赖性钙通道基因（CACNL 1A 4）定位于19 p13。3）SCA 6患者CACNL 1A 4的CAG三核苷酸重复异常扩增。4）CAG重复数与发病年龄呈负相关。SCA 6可能来自同一个共同的祖先，CAG重复序列扩增后转化为多聚谷氨酰胺链，导致选择性神经细胞缺失的原因和机制有待进一步研究。

项目成果

吉木 敬: "難治性血管炎の病因論" 日本皮膚科学会雑誌. 106. 1732-1734 (1997)

Takashi Yoshiki：“难治性血管炎的病因学”日本皮肤病学会杂志 106。1732-1734（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。”

Yabe I.: "SCA6 mutation analysis in a large cohort of the Japanese patients with late-onset pure cerebellar ataxia." J.Neurol.Sc.(印刷中). (1998)

Yabe I.：“大型迟发型小脑性共济失调患者的 SCA6 突变分析”（J.Neurol.Sc）（1998 年出版）。

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）

Yamazaki, H.: "A wide spectrum of collagen vascular and autoimmine diseases in transgenic rats carrying the env-pX gene of human T lymphocyte tropic virus type I." Int.Immunol. 9. 339-346 (1997)

Yamazaki, H.：“携带人类 T 淋巴细胞嗜性病毒 I 型 env-pX 基因的转基因大鼠患有多种胶原血管和自身免疫性疾病。”