Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, 94720, USA.
Memory and Aging Center, UCSF, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.
Acta Neuropathol Commun. 2016 Sep 2;4(1):98. doi: 10.1186/s40478-016-0367-7.
Rare variation in TREM2 has been associated with greater risk for Alzheimer's disease (AD). TREM2 encodes a cell surface receptor expressed on microglia and related cells, and the R47H variant associated with AD appears to affect the ability of TREM2 to bind extracellular ligands. In addition, other rare TREM2 mutations causing early-onset neurodegeneration are thought to impair cell surface expression. Using a sequence kernel association (SKAT) analysis in two independent AD cohorts, we found significant enrichment of rare TREM2 variants not previously characterized at the protein level. Heterologous expression of the identified variants showed that novel variants S31F and R47C displayed significantly reduced cell surface expression. In addition, we identified rare variant R136Q in a patient with language-predominant AD that also showed impaired surface expression. The results suggest rare TREM2 variants enriched in AD may be associated with altered TREM2 function and that AD risk may be conferred, in part, from altered TREM2 surface expression.
TREM2 罕见变异与阿尔茨海默病（AD）的风险增加有关。TREM2 编码一种在小胶质细胞和相关细胞上表达的细胞表面受体，与 AD 相关的 R47H 变体似乎影响了 TREM2 结合细胞外配体的能力。此外，其他导致早发性神经退行性变的罕见 TREM2 突变被认为会损害细胞表面表达。我们使用两个独立的 AD 队列中的序列核关联（SKAT）分析，发现了先前在蛋白质水平上未表征的罕见 TREM2 变异体的显著富集。鉴定出的变体的异源表达表明，新型变体 S31F 和 R47C 显示出明显降低的细胞表面表达。此外，我们在一位以语言为主的 AD 患者中发现了罕见的 R136Q 变体，该变体也表现出表面表达受损。结果表明，AD 中富集的罕见 TREM2 变体可能与 TREM2 功能改变有关，并且 AD 风险可能部分归因于 TREM2 表面表达改变。
