Mutations

TREM2 H157Y

Overview

Pathogenicity: Alzheimer's Disease : Possible Risk Modifier
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr6:41127543 C>T
dbSNP ID: rs2234255
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CAC to TAC
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 3

Findings

Variant rs2234255 (H157Y) was associated with an increased risk for Alzheimer’s disease (AD) in a Han Chinese cohort (odds ratio: 11.01, p = 0.02) (Jiang et al., 2016). Studies of Caucasian (Cuyvers et al., 2014; Ghani et al., 2016; Guerreiro et al., 2013; Jin et al., 2014), Japanese (Miyashita et al., 2014), and African-American (Jin et al., 2015) cohorts failed to detect an association between this variant and AD. However, a meta-analysis of the studies cited above resulted in a significant association (7,102 cases, 7,408 controls, odds ratio 3.65, p = 0.002) (Jiang et al., 2016). Subsequently, the H157Y variant was reported to be associated with AD in a cohort composed of subjects enrolled in the Alzheimer’s Disease Sequencing Project (5575 cases, 4808 controls, odds ratio: 4.7, p = 0.01) (Song et al., 2017), while a large case-control study in Caucasians did not meet the investigators’ threshold for a statistically significant association, p < 10-4 (18,077 cases, 16,097 controls, p = 0.046) (Sims et al., 2017).

No association between H157Y and frontotemporal dementia was found in a Belgian cohort (Cuyvers et al., 2014).

Neuropathology

Neuropathological characterization of individuals carrying the H157Y variant is currently lacking.

Biological Effect

Two independent groups have reported that soluble TREM2 (sTREM2) is generated by protease cleavage after amino acid 157, and that the histidine-to-tyrosine substitution results in increased shedding of sTREM2 (Schlepckow et al., 2017; Thornton et al., 2017). The matrix metalloprotease ADAM10 had been identified previously as one of the sheddases responsible for the generation of sTREM2 (Kleinberger et al., 2014), and both groups confirmed that this enzyme also cleaved the variant form. While one group reported an increase in the level of TREM2 C-terminal fragments (CTF) in the variant, as might be expected to accompany an increased rate of cleavage (Thornton et al., 2017), the other group observed less CTF in lysates of cells expressing H157Y, suggesting enhanced degradation of CTFs (Schlepckow et al., 2017).

The H157Y mutation reduced activation in response to phospholipid ligands in 2B4 T cells engineered to turn on GFP expression when TREM2 was engaged (Song et al., 2017) and also decreased phagocytosis of pHrodo-E.Coli by HEK Flp-in cells expressing the variant (Schlepckow et al., 2017), compared with cells that expressed wild-type TREM2.

Last Updated: 07 Feb 2018

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. . A rare coding variant in TREM2 increases risk for Alzheimer's disease in Han Chinese. Neurobiol Aging. 2016 Jun;42:217.e1-3. Epub 2016 Mar 3 PubMed.
  2. . 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.
  3. . 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.
  4. . TREM2 variants in Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):117-27. Epub 2012 Nov 14 PubMed.
  5. . 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.
  6. . 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.
  7. . TREM2 is associated with increased risk for Alzheimer's disease in African Americans. Mol Neurodegener. 2015 Apr 10;10:19. PubMed.
  8. . TREM2 p.H157Y Variant and the Risk of Alzheimer's Disease: A Meta-Analysis Involving 14,510 Subjects. Curr Neurovasc Res. 2016;13(4):318-320. PubMed.
  9. . 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.
  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. . An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO Mol Med. 2017 Oct;9(10):1356-1365. PubMed.
  12. . TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer's disease-associated H157Y variant. EMBO Mol Med. 2017 Oct;9(10):1366-1378. PubMed.
  13. . TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med. 2014 Jul 2;6(243):243ra86. PubMed.

Further Reading

Protein Diagram

Primary Papers

  1. . A rare coding variant in TREM2 increases risk for Alzheimer's disease in Han Chinese. Neurobiol Aging. 2016 Jun;42:217.e1-3. Epub 2016 Mar 3 PubMed.
  2. . TREM2 p.H157Y Variant and the Risk of Alzheimer's Disease: A Meta-Analysis Involving 14,510 Subjects. Curr Neurovasc Res. 2016;13(4):318-320. PubMed.
  3. . 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.

Alzpedia

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.