Mutations

TREM2 R136Q

Overview

Pathogenicity: Alzheimer's Disease : Not Pathogenic, Frontotemporal Dementia : Unclear Pathogenicity
Clinical Phenotype: Primary Progressive Aphasia (Logopenic Variant)
Reference Assembly: GRCh37 (105)
Position: Chr6:41127605 G>A
dbSNP ID: rs149622783
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: CGG to CAG
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 3

Findings

In three studies of Caucasian cohorts, the R136Q variant was found in one of 281 AD patients and one of 501 controls (odds ratio 1.8, p = 1) (Guerreiro et al., 2013), one of 2047 AD patients and none of 1623 controls (p = 1) (Jin et al., 2014), and in none of 31 AD patients and one of 245 controls (Sirkis et al., 2016).  Subsequently, the variant was not associated with AD in a case-control study of almost 34,000 Caucasian subjects (approximately 18,000 AD and 16,000 controls; odds ratio: 1.66, p = 0.46) (Sims et al., 2017).

The R136Q variant was also found in a patient affected with logopenic variant primary progressive aphasia (Sirkis et al., 2016).

Neuropathology

No data.

Biological Effect

The arginine-to-glutamine substitution at amino acid 136 was predicted to be benign by PolyPhen2, (Guerreiro et al., 2013; Jin et al., 2014).  When heterologously expressed in HEK293 cells, the R136Q variant showed normal protein maturation, although immature forms of R136Q TREM2 migrated somewhat more slowly on SDS-PAGE than did immature forms of wild-type TREM2; in addition, the R136Q variant showed slightly reduced cell-surface expression compared with wild-type (Sirkis et al., 2016).

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. . 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.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . 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.

Other mutations at this position

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