Title | Rare TREM2 variants associated with Alzheimer's disease display reduced cell surface expression. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Sirkis DW, Bonham LW, Aparicio RE, Geier EG, Ramos EMarisa, Wang Q, Karydas A, Miller ZA, Miller BL, Coppola G, Yokoyama JS |
Journal | Acta Neuropathol Commun |
Volume | 4 |
Issue | 1 |
Pagination | 98 |
Date Published | 2016 09 02 |
ISSN | 2051-5960 |
Keywords | Aged, Alzheimer Disease, Case-Control Studies, Cell Membrane, Cohort Studies, Female, Genetic Predisposition to Disease, HEK293 Cells, Humans, Male, Membrane Glycoproteins, Polymorphism, Single Nucleotide, Receptors, Immunologic |
Abstract | 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. |
DOI | 10.1186/s40478-016-0367-7 |
Alternate Journal | Acta Neuropathol Commun |
PubMed ID | 27589997 |
PubMed Central ID | PMC5010724 |
Grant List | P50 AG023501 / AG / NIA NIH HHS / United States K01 AG049152 / AG / NIA NIH HHS / United States P30 NS062691 / NS / NINDS NIH HHS / United States K23 AG048291 / AG / NIA NIH HHS / United States F32 AG050404 / AG / NIA NIH HHS / United States P01 AG019724 / AG / NIA NIH HHS / United States |
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