Mutations

TREM2 D87N

Overview

Pathogenicity: Alzheimer's Disease : Possible Risk Modifier
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr6:41129133 G>A
dbSNP ID: rs142232675
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GAT to AAT
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 2

Findings

The D87N variant was reported to be significantly associated with AD when it was found in six of 1,091 AD patients but in none of 1,105 controls (Guerreiro et al., 2013). Subsequently, an association was found in a cohort from the Alzheimer’s Disease Sequencing Project (5575 cases, 4808 controls, odds ratio 2.3) (Song et al., 2017). However, other studies have failed to confirm this association (Benitez et al., 2013; Borroni et al., 2014; Cuyvers et al., 2014; Ghani et al., 2016; Jin et al., 2014; Jin et al., 2015; Jonsson et al., 2013; Sims et al., 2017). The variant was not found in Japanese subjects (approximately 2,200 cases and 2,500 controls) (Miyashita et al., 2014).

The variant was not associated with frontotemporal dementia in Italian or Belgian cohorts (Borroni et al., 2014; Cuyvers et al., 2014).

Neuropathology

A single AD patient, heterozygous for the D87N variant, has been described. This patient had typical AD pathology, including widespread tau pathology (Braak stage 6) (Guerreiro et al., 2013).

Biological Effect

The D87N variant exhibits normal maturation (Sirkis et al., 2016), and the aspartate to asparagine substitution does not appear to drastically alter folding or promote protein aggregation (Kober et al., 2017). In a cell-free assay, the D87N variant exhibited decreased binding to LDL (47 percent decrease, compared with wild-type TREM2), lipidated clusterin (40 percent decrease), and lipidated ApoE (52 percent decrease); uptake of acetylated LDL was reduced in HEK293 cells expressing the D87N variant compared with cells expressing wild-type TREM2 (Yeh et al., 2016). However, this variant increased activation by purified phospholipids, HDL, and LDL in reporter cells engineered to turn on GFP expression when TREM2 is engaged (Song et al., 2017).

Last Updated: 07 Feb 2018

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References

Paper Citations

  1. . TREM2 variants in Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):117-27. Epub 2012 Nov 14 PubMed.
  2. . Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement. 2017 Apr;13(4):381-387. Epub 2016 Aug 9 PubMed.
  3. . TREM2 is associated with the risk of Alzheimer's disease in Spanish population. Neurobiol Aging. 2013 Jun;34(6):1711.e15-7. Epub 2013 Feb 5 PubMed.
  4. . Heterozygous TREM2 mutations in frontotemporal dementia. Neurobiol Aging. 2014 Apr;35(4):934.e7-10. Epub 2013 Oct 16 PubMed.
  5. . Investigating the role of rare heterozygous TREM2 variants in Alzheimer's disease and frontotemporal dementia. Neurobiol Aging. 2014 Mar;35(3):726.e11-9. Epub 2013 Oct 9 PubMed.
  6. . Mutation analysis of the MS4A and TREM gene clusters in a case-control Alzheimer's disease data set. Neurobiol Aging. 2016 Jun;42:217.e7-217.e13. Epub 2016 Mar 21 PubMed.
  7. . Coding variants in TREM2 increase risk for Alzheimer's disease. Hum Mol Genet. 2014 Nov 1;23(21):5838-46. Epub 2014 Jun 4 PubMed.
  8. . TREM2 is associated with increased risk for Alzheimer's disease in African Americans. Mol Neurodegener. 2015 Apr 10;10:19. PubMed.
  9. . Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):107-16. Epub 2012 Nov 14 PubMed.
  10. . Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nat Genet. 2017 Sep;49(9):1373-1384. Epub 2017 Jul 17 PubMed.
  11. . Lack of genetic association between TREM2 and late-onset Alzheimer's disease in a Japanese population. J Alzheimers Dis. 2014;41(4):1031-8. PubMed.
  12. . Rare TREM2 variants associated with Alzheimer's disease display reduced cell surface expression. Acta Neuropathol Commun. 2016 Sep 2;4(1):98. PubMed.
  13. . Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. Elife. 2016 Dec 20;5 PubMed.
  14. . TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron. 2016 Jul 20;91(2):328-40. PubMed.

Further Reading

Protein Diagram

Primary Papers

  1. . TREM2 variants in Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):117-27. Epub 2012 Nov 14 PubMed.

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