CAG repeat expansion in the TATA box-binding protein gene causes autosomal dominant cerebellar ataxia
CAG repeat expansion in the TATA box-binding protein gene causes autosomal dominant cerebellar ataxia
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DOI：
10.1093/brain/124.10.1939
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发表时间：
2001-10-01
期刊：
影响因子：
14.5
通讯作者：
Brice, A
中科院分区：
文献类型：
--
作者：
Fujigasaki, H;Martin, JJ;Brice, A
至少有13个基因座负责常染色体显性小脑性共济失调（ADCA）已被确定。脊髓小脑性共济失调1、2、3、6和7是由翻译的CAG重复扩增引起的。然而，在法国，>30%的ADCA不能由已知基因解释。最近，TATA盒结合蛋白（TBP）基因，已知含有CAG/CAA重复的转录因子之一，在进行性小脑共济失调患者的分析显示，一个散发的情况下，63个重复。我们在162例ADCA指数病例中检测了该基因。一个扩展的重复与46个重复单位被检测到在一个单一的索引案件从比利时。在这个家庭中，两个受影响的成员和六个未受影响的，但在风险，个人携带扩展的等位基因。有趣的是，扩展的重复序列在传输过程中是稳定的。6例患者的主要临床特征为小脑性共济失调、痴呆和行为障碍，发病年龄在40 ~ 60岁。主要的神经病理学发现是严重的神经元丢失和浦肯野细胞层神经胶质增生。免疫组化分析显示，神经元核内包涵体含有扩大的多聚谷氨酰胺，表明这种疾病与其他多聚谷氨酰胺疾病的几个特点。这项研究表明，TBP基因中的CAG/CAA重复扩增会导致ADCA伴痴呆和/或精神病表现。
At least 13 loci responsible for autosomal dominant cerebellar ataxia (ADCA) have been identified. Spinocerebellar ataxia 1, 2, 3, 6 and 7 are caused by translated CAG repeat expansions. However, in France, >30% of ADCAs are not explained by the known genes. Recently, analysis of the TATA box-binding protein (TBP) gene, one of the transcription factors known to contain a CAG/CAA repeat, in patients with progressive cerebellar ataxia revealed one sporadic case with 63 repeats. We examined this gene in 162 index cases with ADCA. An expanded repeat with 46 repeat units was detected in a single index case from Belgium. In this family, two affected members and six unaffected, but at-risk, individuals carried expanded alleles. Interestingly, the expanded repeat was stable during transmission. The main clinical features in six patients were cerebellar ataxia, dementia and behavioural disturbances with onset in their fourth to sixth decade. The main neuropathological finding was severe neuronal loss and gliosis in the Purkinje cell layer. Immunohistochemical analysis showed neuronal intranuclear inclusions containing expanded polyglutamine, indicating that this disease shares several features with other polyglutamine diseases. This study demonstrates that CAG/CAA repeat expansion in the TBP gene causes ADCA with dementia and/or psychiatric manifestations.