Closing the tau loop: the missing tau mutation
Closing the tau loop: the missing tau mutation
复制标题
DOI：
10.1093/brain/awv234
复制
发表时间：
2015-10-01
期刊：
影响因子：
14.5
通讯作者：
Lynch, Tim
中科院分区：
文献类型：
--
作者：
McCarthy, Allan;Lonergan, Roisin;Lynch, Tim
额颞叶变性包括一组以行为、执行、语言障碍为特征的疾病，有时还具有帕金森综合征和运动神经元疾病的特征。1994年，我们描述了一个与17号染色体相关的额颞叶痴呆的爱尔兰裔美国人家族，该家族与广泛的tau病理学相关。我们将这种现象命名为“去抑制-痴呆-帕金森-肌萎缩综合征”。我们随后确定了MAPT基因的突变。除了外显子10的5'剪接位点外，随着时间的推移鉴定出11个MAPT基因剪接位点茎环突变。我们最近确定了另一个爱尔兰家庭与常染色体显性遗传性早期遗忘症和行为改变或帕金森症与'失踪' +15突变的内含子边界的外显子10。我们对先证者和四个兄弟姐妹（包括两个受影响的兄弟姐妹）进行了临床、神经心理学和神经影像学研究。我们对MAPT进行了测序并进行了分离分析。我们通过对从用外显子捕获构建体转染的人胚肾细胞中提取的RNA进行实时聚合酶链反应分析来寻找tau变体的生物学效应。我们在所有受影响的受试者中发现了c.915+ 15 A>C外显子10/内含子10茎环突变，但未在未受影响的受试者中发现。c.915+ 15 A>C变异体导致tau剪接模式转变为主要的外显子10+模式，推测导致主要的4个重复tau和很少的3个重复tau。这强烈表明c.915+ 15 A>C变异是一种突变，它通过将tau转录和翻译转移到+4重复tau而导致该家系中与17号染色体相关的额颞叶痴呆。Tau（MAPT）筛查应考虑在家族中的健忘症或非典型帕金森病与行为障碍并存的疾病过程的早期。我们描述了15年前预测的最终缺失的茎环tau突变。当首次提出茎环模型时，现在已经在“茎”内的所有预测位点处鉴定出突变，并且如预期的那样在“环”区域内没有发现突变。因此，我们在21年前“打开循环”之后“关闭tau循环”。
Frontotemporal lobar degeneration comprises a group of disorders characterized by behavioural, executive, language impairment and sometimes features of parkinsonism and motor neuron disease. In 1994 we described an Irish-American family with frontotemporal dementia linked to chromosome 17 associated with extensive tau pathology. We named this disinhibition-dementia-parkinsonism-amyotrophy complex. We subsequently identified mutations in the MAPT gene. Eleven MAPT gene splice site stem loop mutations were identified over time except for 5' splice site of exon 10. We recently identified another Irish family with autosomal dominant early amnesia and behavioural change or parkinsonism associated with the 'missing' +15 mutation at the intronic boundary of exon 10. We performed a clinical, neuropsychological and neuroimaging study on the proband and four siblings, including two affected siblings. We sequenced MAPT and performed segregation analysis. We looked for a biological effect of the tau variant by performing real-time polymerase chain reaction analysis of RNA extracted from human embryonic kidney cells transfected with exon trapping constructs. We found a c.915+15A>C exon 10/intron 10 stem loop mutation in all affected subjects but not in the unaffected. The c.915+15A>C variant caused a shift in tau splicing pattern to a predominantly exon 10+ pattern presumably resulting in predominant 4 repeat tau and little 3 repeat tau. This strongly suggests that the c.915+15A>C variant is a mutation and that it causes frontotemporal dementia linked to chromosome 17 in this pedigree by shifting tau transcription and translation to +4 repeat tau. Tau (MAPT) screening should be considered in families where amnesia or atypical parkinsonism coexists with behavioural disturbance early in the disease process. We describe the final missing stem loop tau mutation predicted 15 years ago. Mutations have now been identified at all predicted sites within the 'stem' when the stem-loop model was first proposed and no mutations have been found within the 'loop' region as expected. Therefore we 'close the tau loop' having 'opened the loop' 21 years ago.