The Alzheimer's associated 5' region of the SORL1 gene cis regulates SORL1 transcripts expression.
The Alzheimer's associated 5' region of the SORL1 gene cis regulates SORL1 transcripts expression.
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DOI：
10.1016/j.neurobiolaging.2010.10.004
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发表时间：
2012-07
影响因子：
4.2
通讯作者：
Chiba-Falek O
中科院分区：
文献类型：
--
作者：
McCarthy JJ;Saith S;Linnertz C;Burke JR;Hulette CM;Welsh-Bohmer KA;Chiba-Falek O
SORL1已被确定为迟发性阿尔茨海默病（LOAD）的主要因素。我们测试了SORL1基因5 '的遗传变异是否通过调节SORL1 mrna的表达和剪接来调节发生LOAD的风险。对来自92名神经正常个体的144个脑样本进行了两种不同的易受LOAD病理影响的脑结构检查。与非携带者相比，携带rs7945931和rs2298525位点小等位基因的颞叶皮层更容易受到阿尔茨海默病的影响，其sorl1 - mrna水平增加了约2倍。在额叶皮层中未检测到基因对总sorl1 mrna水平的影响。然而，rs11600875小等位基因与显着增加的外显子2跳跃水平相关，但仅在额叶皮层。额叶和颞叶皮层间sorl1 - mrna表达无相关性。总的来说，表明SORL1表达的遗传调控的脑区域特异性。我们的研究结果表明，SORL1表达的遗传调控在疾病风险中发挥作用，并可能负责报道的load关联。有必要进一步研究以检测实际的致病变异。
SORL1 has been identified as a major contributor to Late-Onset Alzheimer’s disease (LOAD). We test whether genetic variability in the 5′of SORL1 gene modulates the risk to develop LOAD via regulation of SORL1-mRNA expression and splicing. Two brain structures, differentially vulnerable to LOAD pathology, were examined in 144 brain samples from 92 neurologically normal individuals. The temporal cortex, which is more susceptible to Alzheimer’s pathology, demonstrated ~2-fold increase in SORL1-mRNAs levels in carriers of the minor alleles at SNPs, rs7945931 and rs2298525, compared to non-carriers. No genetic effect on total-SORL1-mRNA levels was detected in the frontal-cortex. However, rs11600875 minor allele was associated with significantly increased levels of exon-2 skipping, but only in frontal cortex. No correlation of SORL1-mRNAs expression was found between frontal and temporal cortexes. Collectively, indicating the brain-region specificity of the genetic regulation of SORL1 expression. Our results suggest that genetic regulation of SORL1 expression plays a role in disease risk and maybe responsible for the reported LOAD-associations. Further studies to detect the actual pathogenic variant/s are necessary.
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剪接的组织特异性遗传控制：对复杂性状的研究的影响。
影响因子：
9.8
作者：
Heinzen EL;Ge D;Cronin KD;Maia JM;Shianna KV;Gabriel WN;Welsh-Bohmer KA;Hulette CM;Denny TN;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
4.8
作者：
Jacobsen, L;Madsen, P;Petersen, CM
通讯作者：
Petersen, CM
DOI：
10.1097/01.jnen.0000228205.19915.20
发表时间：
2006-09-01
影响因子：
3.2
作者：
Dodson, Sara E.;Gearing, Marla;Lah, James J.
通讯作者：
Lah, James J.
DOI：
10.1073/pnas.0503689102
发表时间：
2005-09-20
影响因子：
11.1
作者：
Andersen, OM;Reiche, J;Willnow, TE
通讯作者：
Willnow, TE
影响因子：
4.8
作者：
Schmidt, Vanessa;Sporbert, Anje;Willnow, Thomas E.
通讯作者：
Willnow, Thomas E.