Overview

Pathogenicity: Alzheimer's Disease : Benign, Frontotemporal Dementia : Unclear Pathogenicity
Clinical Phenotype: Primary Progressive Aphasia, Progressive Nonfluent Aphasia
Position: (GRCh38/hg38):Chr6:41161571 C>T
Position: (GRCh37/hg19):Chr6:41129309 C>T
dbSNP ID: rs2234252
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCG to GTG
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 2

Findings

The A28V variant was found in one Alzheimer’s patient in a Caucasian cohort from the Alzheimer’s Disease Sequencing Project (2927 AD, 2633 cognitively healthy controls) (Sirkis et al., 2016). Subsequently, the variant was not associated with AD in a case-control study of more than 33,000 Caucasian subjects (approximately 18,000 AD and 16,000 controls; odds ratio: 2.56, p = 0.3) (Sims et al., 2017).

The A28V variant was also found in a Spanish patient affected with frontotemporal dementia (primary progressive aphasia, non-fluent variant) (Thelen et al., 2014).

Neuropathology

No data.

Biological Effect

The A28 variant underwent normal maturation but showed increased cell-surface expression when heterologously expressed in HEK293 cells (Sirkis et al., 2016).

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References

Paper Citations

1. Sirkis DW, Bonham LW, Aparicio RE, Geier EG, Ramos EM, Wang Q, Karydas A, Miller ZA, Miller BL, Coppola G, Yokoyama JS. Rare TREM2 variants associated with Alzheimer's disease display reduced cell surface expression. Acta Neuropathol Commun. 2016 Sep 2;4(1):98. PubMed.
2. 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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.
3. Thelen M, Razquin C, Hernández I, Gorostidi A, Sánchez-Valle R, Ortega-Cubero S, Wolfsgruber S, Drichel D, Fliessbach K, Duenkel T, Damian M, Heilmann S, Slotosch A, Lennarz M, Seijo-Martínez M, Rene R, Kornhuber J, Peters O, Luckhaus C, Jahn H, Hüll M, Rüther E, Wiltfang J, Lorenzo E, Gascon J, Lleó A, Lladó A, Campdelacreu J, Moreno F, Ahmadzadehfar H, Dementia Genetics Spanish Consortium (DEGESCO), Fortea J, Indakoetxea B, Heneka MT, Wetter A, Pastor MA, Riverol M, Becker T, Frölich L, Tárraga L, Boada M, Wagner M, Jessen F, Maier W, Clarimón J, López de Munain A, Ruiz A, Pastor P, Ramirez A. 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.

Further Reading

No Available Further Reading