Potential late-onset Alzheimer's disease-associated mutations in the ADAM10 gene attenuate α-secretase activity
Potential late-onset Alzheimer's disease-associated mutations in the ADAM10 gene attenuate α-secretase activity
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DOI：
10.1093/hmg/ddp323
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发表时间：
2009-10-15
影响因子：
3.5
通讯作者：
Tanzi, Rudolph E.
中科院分区：
文献类型：
--
作者：
Kim, Minji;Suh, Jaehong;Tanzi, Rudolph E.
解整合素金属蛋白酶10（ADAM10）是解整合素和金属蛋白酶家族的成员，是一种α-分泌酶，能够对淀粉样前体蛋白进行抗淀粉样蛋白生成的蛋白水解作用。在此，我们提供了ADAM10与阿尔茨海默病（AD）存在遗传关联的证据，以及在ADAM10前结构域中两个罕见的可能与疾病相关的非同义突变，Q170H和R181G。这些突变在来自7个晚发性AD家族的16名患病个体中的11人身上被发现（平均发病年龄为69.5岁）。每个突变也在一名未患病个体中被发现，这意味着外显率不完全。在功能上，在基于细胞的研究中，这两个突变都显著减弱了ADAM10的α-分泌酶活性（降低>70%），并提高了Aβ水平（1.5 - 3.5倍）。总之，我们提供了ADAM10作为候选AD易感基因的首个证据，并报告了两个对晚发性家族性AD具有不完全外显率的潜在致病性突变。
ADAM10, a member of a disintegrin and metalloprotease family, is an alpha-secretase capable of anti-amyloidogenic proteolysis of the amyloid precursor protein. Here, we present evidence for genetic association of ADAM10 with Alzheimer's disease (AD) as well as two rare potentially disease-associated non-synonymous mutations, Q170H and R181G, in the ADAM10 prodomain. These mutations were found in 11 of 16 affected individuals (average onset age 69.5 years) from seven late-onset AD families. Each mutation was also found in one unaffected subject implying incomplete penetrance. Functionally, both mutations significantly attenuated alpha-secretase activity of ADAM10 (> 70% decrease), and elevated A beta levels (1.5-3.5-fold) in cell-based studies. In summary, we provide the first evidence of ADAM10 as a candidate AD susceptibility gene, and report two potentially pathogenic mutations with incomplete penetrance for late-onset familial AD.