The role of MAPT sequence variation in mechanisms of disease susceptibility
The role of MAPT sequence variation in mechanisms of disease susceptibility
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DOI：
10.1042/bst20120063
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发表时间：
2012-08-01
影响因子：
3.9
通讯作者：
Wade-Martins, Richard
中科院分区：
文献类型：
--
作者：
Caffrey, Tara M.;Wade-Martins, Richard
微管相关蛋白tau（MAPT或tau）在神经退行性疾病领域中引起了极大的兴趣，因为在MAPT基因座和tau蛋白病（一组不同的神经退行性痴呆和运动障碍）之间存在明确的遗传联系。跨越MAPT基因座的区域中的基因组结构包含类似于1.8 Mb的连锁不平衡块，其特征在于两个主要单倍型：H1和H2。最近的研究已经确定了MAPT基因座和神经退行性疾病之间的强遗传关联，并揭示了MAPT转录本的表达和选择性剪接的单倍型特异性差异。整合遗传关联数据和基因表达数据以了解基因位点的非编码遗传变异如何影响基因表达并导致对疾病的易感性是疾病遗传学的高度优先事项，MAPT位点为此提供了一个很好的范例。在不存在由单倍型序列变异引起的蛋白质编码变化的情况下，蛋白质表达水平的改变或同种型表达比率的改变是将MAPT遗传疾病与生物学功能联系起来的极好的候选机制。需要使用新的转基因和内源性遗传模型来理解MAPT序列变异在疾病易感性机制中的作用。
The microtubule-associated protein tau (MAPT or tau) is of great interest in the field of neurodegeneration as there is a well-established genetic link between the MAPT gene locus and tauopathies, a diverse group of neurodegenerative dementias and movement disorders. The genomic architecture in the region spanning the MAPT locus contains a similar to 1.8 Mb block of linkage disequilibrium characterized by two major haplotypes: H1 and H2. Recent studies have established strong genetic association between the MAPT locus and neurodegenerative disease and uncovered haplotype-specific differences in expression and alternative splicing of MAPT transcripts. Integrating genetic association data and gene expression data to understand how non-coding genetic variation at a gene locus affects gene expression and leads to susceptibility to disease is a high priority in disease genetics, and the MAPT locus provides an excellent paradigm for this. In the absence of protein-coding changes caused by haplotype sequence variation, altered levels of protein expression or altered ratios of isoform expression are excellent candidate mechanisms to link the MAPT genetic disease association with biological function. The use of novel transgenic and endogenous genetic models are required to understand the role of MAPT sequence variation in mechanisms of disease susceptibility.