Mutations

TREM2 E151K

Overview

Pathogenicity: Alzheimer's Disease : Not Pathogenic
Clinical Phenotype:
Reference Assembly: GRCh37 (105)
Position: Chr6:41127561 G>A
dbSNP ID: rs79011726
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GAG to AAG
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 3

Findings

The E151K variant did not associate with Alzheimer’s disease in Icelanders (3550 AD, 8888 elderly controls; odds ratio: 1.21, p = 0.59) (Jonsson et al., 2013), or in two other Caucasian cohorts (total approximately 5000 AD patients, 4000 controls) (Jin et al., 2014; Sirkis et al., 2016). Subsequently, the variant did not associate with AD in a case-control study of almost 34,000 Caucasian subjects (approximately 18,000 AD and 16,000 controls; odds ratio: 0.79, p = 0.63) (Sims et al., 2017). Nor did the variant associate with AD in a study of African-Americans, where it was found in six of 867 Alzheimer’s patients and seven of 2467 controls (p = 0.22) (Jin et al., 2015).

Neuropathology

No data.

Biological Effect

The glutamate-to-lysine substitution at amino acid 151 was predicted by PolyPhen to be damaging (Jin et al., 2014; Jin et al., 2015) but by SIFT to be tolerated (Jin et al., 2015).

When heterologously expressed in HEK 293 cells, the E151K variant exhibited normal protein maturation but a reduction in overall expression compared with wild-type TREM2 (Sirkis, et al., 2016). When stimulated by purified phospholipids, reporter cells expressing the E151K variant responded similarly to cells expressing wild-type TREM2 (Song et al., 2017).

 

Last Updated: 07 Feb 2018

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References

Paper Citations

  1. . 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.
  2. . 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.
  3. . Rare TREM2 variants associated with Alzheimer's disease display reduced cell surface expression. Acta Neuropathol Commun. 2016 Sep 2;4(1):98. PubMed.
  4. . 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.
  5. . TREM2 is associated with increased risk for Alzheimer's disease in African Americans. Mol Neurodegener. 2015 Apr 10;10:19. PubMed.
  6. . 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . 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.
  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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