Overview

Pathogenicity: Alzheimer's Disease : Possible Risk Modifier, Frontotemporal Dementia : Possible Risk Modifier
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia
Position: (GRCh38/hg38):Chr6:41158917 T>C
Position: (GRCh37/hg19):Chr6:41126655 T>C
dbSNP ID: rs2234256
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTG to CCG
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 4

Findings

The rs2234256 (L211P) variant was reported to be associated with an increased risk for Alzheimer’s disease in African Americans (OR 1.27, p = 0.01) (Jin et al., 2015). A significant association between the L211P variant and AD was not found in cohorts of European descent (Cuyvers et al., 2014; Guerreiro et al., 2013; Jin et al., 2014; Sims et al., 2017) or in the multi-ethnic Alzheimer’s Disease Sequencing Project (Song et al., 2017).

The L211P variant appears to be in linkage disequilibrium with two other TREM2 variants: rs2234253 (T96K ) (Cuyvers et al., 2014; Jin et al., 2015; Piccio et al., 2016; Song et al., 2017; Thelen et al., 2014) and rs2234258 (W191X) (Jin et al., 2015). It should be noted that although the L211P and W191X variants were found to be linked in the African American cohort studied by Jin et al., the association between L211P and AD risk persisted when the analysis was adjusted for the presence of W191X (Jin et al., 2015).

The L211P variant was found in two German and four Spanish frontotemporal dementia patients, all of whom also carried the T96K variant (Thelen et al., 2014). An association analysis between FTD risk and L211P was not performed in this study, due to the linkage with T96K, which was found to significantly associate with FTD.

Neuropathology

Unknown. Levels of soluble TREM2 in CSF were lower in carriers of the T96K/W191X/L211P variants than in noncarriers (all CDR=0) (Piccio et al., 2016).

Biological Effect

In silico, this variant is predicted by SIFT to be tolerated and by PolyPhen-2 to be benign (Jin et al., 2015). Activation by purified phospholipids did not differ between cells expressing L211P and wild-type TREM2 in a reporter cell line engineered to turn on GFP expression when TREM2 was engaged (Song et al., 2017).

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References

Paper Citations

1. Jin SC, Carrasquillo MM, Benitez BA, Skorupa T, Carrell D, Patel D, Lincoln S, Krishnan S, Kachadoorian M, Reitz C, Mayeux R, Wingo TS, Lah JJ, Levey AI, Murrell J, Hendrie H, Foroud T, Graff-Radford NR, Goate AM, Cruchaga C, Ertekin-Taner N. TREM2 is associated with increased risk for Alzheimer's disease in African Americans. Mol Neurodegener. 2015 Apr 10;10:19. PubMed.
2. 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.
3. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton A, Hardy J, Alzheimer Genetic Analysis Group. TREM2 variants in Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):117-27. Epub 2012 Nov 14 PubMed.
4. 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.
5. Song W, Hooli B, Mullin K, Jin SC, Cella M, Ulland TK, Wang Y, Tanzi RE, Colonna M. 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.
6. Piccio L, Deming Y, Del-Águila JL, Ghezzi L, Holtzman DM, Fagan AM, Fenoglio C, Galimberti D, Borroni B, Cruchaga C. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 2016 Jun;131(6):925-33. Epub 2016 Jan 11 PubMed.
7. 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.

Other Citations

1. T96K

Further Reading

No Available Further Reading