Overview

Pathogenicity: Alzheimer's Disease : Benign, Frontotemporal Dementia : Unclear Pathogenicity
Position: (GRCh38/hg38):Chr6:41158881 C>T
Position: (GRCh37/hg19):Chr6:41126619 C>T
dbSNP ID: rs138355759
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACT to ATT
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 4

Findings

In a North American Caucasian cohort, the T223I variant was found in two of 2077 Alzheimer’s patients and none of 1642 controls (p = 0.51) (Jin et al., 2014). This variant was also found in one of 245 controls but none of 31 Alzheimer’s patients in a Caucasian discovery series (Sirkis et al., 2016). In a Belgian study, the variant was found in one of 1216 AD patients, none of 359 FTD patients, and two of 1094 controls (Cuyvers et al., 2014). Subsequently, the variant was not associated with AD in a case-control study of nearly 34,000 Caucasian subjects (approximately 18,000 AD and 16,000 controls; odds ratio: 1.02, p = 0.96) (Sims et al., 2017).

Neuropathology

No data.

Biological Effect

The T223I variant was predicted by Polyphen2 to be benign (Cuyvers et al., 2014; Jin et al., 2014), by SIFT to be tolerated and by SNPs&Go to be neutral (Cuyvers et al., 2014).

When heterologously expressed in HEK293 cells, T223I TREM2 exhibited normal protein maturation, although immature forms of the T223I variant migrated slightly faster on SDS-PAGE than immature forms of the wild-type protein (Sirkis, et al., 2016).

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References

Paper Citations

1. Jin SC, Benitez BA, Karch CM, Cooper B, Skorupa T, Carrell D, Norton JB, Hsu S, Harari O, Cai Y, Bertelsen S, Goate AM, Cruchaga C. 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. 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.
3. Cuyvers E, Bettens K, Philtjens S, Van Langenhove T, Gijselinck I, van der Zee J, Engelborghs S, Vandenbulcke M, Van Dongen J, Geerts N, Maes G, Mattheijssens M, Peeters K, Cras P, Vandenberghe R, De Deyn PP, Van Broeckhoven C, Cruts M, Sleegers K, BELNEU consortium. 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.
4. 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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.

Further Reading

No Available Further Reading