High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease
High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease
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DOI：
10.1038/mp.2012.15
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发表时间：
2012-09-01
影响因子：
11
通讯作者：
Campion, D.
中科院分区：
文献类型：
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作者：
Pottier, C.;Hannequin, D.;Campion, D.
对14例已知基因（淀粉样前体蛋白（APP）、早老素1（PSEN 1）和早老素2（PSEN 2））无突变的常染色体显性早发性阿尔茨海默病（ADEOAD）指数病例进行外显子组测序，我们发现在5例患者中，SORL 1基因含有未知的无义（n = 1）或错义（n = 4）突变。这些突变在1500名相同种族的对照中未检索到。在包括15例ADEOAD病例的复制样本中，检索到2个未知的非同义突变（1个错义突变，1个无义突变），因此在合并样本中总共产生7/29个未知突变。使用计算机预测，我们得出结论，这七个私人突变可能具有致病作用。SORL 1编码分拣蛋白相关受体LR 11/SorLA，一种参与控制淀粉样β肽产生的蛋白质。我们的研究结果表明，除了APP和PSEN基因的参与，进一步的遗传异质性，涉及另一个基因的相同途径是目前在ADEOAD。Molecular Psychiatry（2012）17，875-879; doi：10.1038/mp.2012.15; 2012年4月3日在线发表
Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n = 1) or missense (n = 4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD. Molecular Psychiatry (2012) 17, 875-879; doi:10.1038/mp.2012.15; published online 3 April 2012