title: Rare TREM2 variants associated with Alzheimer's disease display reduced cell surface expression.
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.
authors: Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, 94720, USA.
authors: Daniel W
authors: DW
authors: Sirkis
authors: Memory and Aging Center, UCSF, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.
authors: Luke W
authors: LW
authors: Bonham
authors: Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, 94720, USA.
authors: Renan E
authors: RE
authors: Aparicio
authors: Memory and Aging Center, UCSF, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.
authors: Ethan G
authors: EG
authors: Geier
authors: Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, The David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA.
authors: Eliana Marisa
authors: EM
authors: Ramos
authors: Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, The David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA.
authors: Qing
authors: Q
authors: Wang
authors: Memory and Aging Center, UCSF, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.
authors: Anna
authors: A
authors: Karydas
authors: Memory and Aging Center, UCSF, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.
authors: Zachary A
authors: ZA
authors: Miller
authors: Memory and Aging Center, UCSF, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.
authors: Bruce L
authors: BL
authors: Miller
authors: Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, The David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA.
authors: Giovanni
authors: G
authors: Coppola
authors: Memory and Aging Center, UCSF, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA. jennifer.yokoyama@ucsf.edu.
authors: Jennifer S
authors: JS
authors: Yokoyama
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002462:Cell Membrane / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human
keywords: Alzheimer’s disease; Genetics; Nasu-Hakola disease; TREM2