Mutations

TREM2 R62H

Overview

Pathogenicity: Alzheimer's Disease : Risk Modifier
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr6:41129207 G>A
dbSNP ID: rs143332484
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CGT to CAT
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 2

Findings

The rs143332484 (R62H) variant was identified as a significant risk modifier for Alzheimer’s disease in a cohort of European-American descent (odds ratio 2.36, p = 2.36 X 10-4) (Jin et al., 2014) and in a cohort from the Alzheimer’s Disease Sequencing Project (odds ratio 1.44, p = 0.001) (Song et al., 2017), while several other studies of European and American subjects did not find an association between the R62H variant and AD (Benitez et al., 2013; Borroni et al., 2014; Cuyvers et al., 2014; Guerreiro et al., 2013; Jonsson et al., 2013; Pottier et al., 2013; Thelen et al., 2014). However, a three-stage case-control study of 48,343 AD cases and 36,790 controls provided strong evidence for an association between the R62H variant and AD risk in Caucasians (odds ratio 1.67, p = 1.55 X 10-14) (Sims et al., 2017).

This variant did not associate with AD risk specifically in African-Americans, possibly due to its very low frequency (Jin et al., 2015).

Whether the R62H variant influences the clinical presentation and/or progression of AD is not known.

In a group of individuals without dementia, levels of soluble TREM2 in cerebrospinal fluid did not differ between R62H carriers (N=10, CDR 0-0.5) and non-carriers (N=95, CDR 0) (Piccio et al., 2016).

The R62H variant did not associate with frontotemporal dementia in three European cohorts (Borroni et al., 2014; Cuyvers et al., 2014; Thelen et al., 2014).

Neuropathology

Post-mortem samples from AD patients carrying the R62H variant displayed reduced microglial coverage of amyloid plaques (Krasemann et al., 2017) and an increased accumulation of autophagosomes in microglia (Ulland et al., 2017) compared to samples from patients with the reference allele.

Biological Effect

The arginine-to-histidine substitution in TREM2 appears to impair ligand binding and subsequent TREM2-mediated processes.

The R62H variant does not alter protein conformation or cell-surface expression, although it may cause subtle changes in protein stability (Kober et al., 2016). This variant exhibited reduced binding to lipoproteins in cell-free assays (Yeh et al., 2016). Uptake of acetylated low-density lipoprotein particles was reduced in HEK293 cells that expressed the R62H variant compared with cells expressing wild-type TREM2, and monocyte-derived macrophages from R62H carriers showed reduced uptake of LDL-Aβ complexes compared with cells derived from age-, gender-, ethnicity- matched controls homozygous for the common allele (Yeh et al., 2016). The R62H mutation somewhat reduced activation in response to purified phospholipids in a reporter cell line engineered to turn on GFP expression when TREM2 is engaged (Song et al., 2017).

The soluble fragment (sTREM2) produced by proteolytic processing of the R62H variant was slightly less effective than wild-type sTREM2 in stimulating microglial production of pro-inflammatory cytokines and in promoting microglial survival after trophic factor withdrawal (Zhong et al., 2017).

Last Updated: 07 Feb 2018

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References

Paper Citations

  1. . 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.
  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. . TREM2 variants in Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):117-27. Epub 2012 Nov 14 PubMed.
  7. . 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.
  8. . TREM2 R47H variant as a risk factor for early-onset Alzheimer's disease. J Alzheimers Dis. 2013;35(1):45-9. PubMed.
  9. . Investigation of the role of rare TREM2 variants in frontotemporal dementia subtypes. Neurobiol Aging. 2014 Nov;35(11):2657.e13-2657.e19. Epub 2014 Jun 20 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. . TREM2 is associated with increased risk for Alzheimer's disease in African Americans. Mol Neurodegener. 2015 Apr 10;10:19. PubMed.
  12. . Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 2016 Jun;131(6):925-33. Epub 2016 Jan 11 PubMed.
  13. . The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity. 2017 Sep 19;47(3):566-581.e9. PubMed.
  14. . TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease. Cell. 2017 Aug 10;170(4):649-663.e13. PubMed.
  15. . Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. Elife. 2016 Dec 20;5 PubMed.
  16. . 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.
  17. . Soluble TREM2 induces inflammatory responses and enhances microglial survival. J Exp Med. 2017 Mar 6;214(3):597-607. Epub 2017 Feb 16 PubMed.

Further Reading

Protein Diagram

Primary Papers

  1. . 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.
  2. . 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.

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