Overview

Pathogenicity: Frontotemporal Dementia : Possible Risk Modifier
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr6:41161367 C>A
Position: (GRCh37/hg19):Chr6:41129105 C>A
dbSNP ID: rs2234253
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACG to AAG
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 2

Findings

The rs2234253 (T96K) variant was reported to be associated with an increased risk for frontotemporal dementia in a Spanish/German cohort (OR 4.23, p = 0.013) (Thelen et al., 2014) but not in an Italian cohort (Borroni et al., 2014). It should be noted that in the former study, all six patients carrying the T96K variant also carried the TREM2 L211P variant. Linkage disequilibrium between the T96K and L211P variants was confirmed in data sets from the Alzheimer’s Disease Sequencing Project and the NIMH AD Genetics Initiative Study (Song et al., 2017), in a Belgian cohort (Cuyvers et al., 2014), in a study including North American and Italian subjects (Piccio et al., 2016), and in two African American cohorts (Jin et al., 2015). It has also been reported that T96K is in linkage disequilibrium with TREM2 variant W191X (rs2234258) (Piccio et al., 2016).

No association between the T96K variant and Alzheimer’s disease was found in several studies (Borroni et al., 2014; Cuyvers et al., 2014; Guerreiro et al., 2013; Jin et al., 2014; Song et al., 2017). The variant was not found in Japanese subjects (approximately 2,200 cases and 2,500 controls) (Miyashita et al., 2014).

The variant was not found in 512 Parkinson’s disease patients or 512 controls in a study of Han Chinese (Tan et al., 2016).

Neuropathology

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

Biological Effect

The threonine-to-lysine substitution does not appear to alter folding or promote protein aggregation, although the variant may exhibit a subtle change in stability compared with the wild-type protein (Kober et al., 2017). Somewhat lower surface expression of the variant, compared to wild-type TREM2, has been reported in cells stably expressing TREM2 along with the adaptor protein TYROBP/DAP12 (Song et al., 2017).

The T96K mutation appears to alter ligand binding. Although wild-type TREM2 and the T96K variant did not differ in a direct lipid binding assay, the variant exhibited significantly increased binding to N2A and THP-1 cells (Kober et al., 2017). Further, the T96K mutation led to increased activation by purified phospholipids, HDL, and LDL in reporter cells engineered to turn on GFP expression when TREM2 is engaged (Song et al., 2017). The T96K mutation was found to be located adjacent to a conserved basic surface on the TREM2 protein that has been implicated in ligand binding, suggesting a “structural explanation” for the variant’s gain of function (Kober et al., 2017).

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References

Paper Citations

1. 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.
2. Borroni B, Ferrari F, Galimberti D, Nacmias B, Barone C, Bagnoli S, Fenoglio C, Piaceri I, Archetti S, Bonvicini C, Gennarelli M, Turla M, Scarpini E, Sorbi S, Padovani A. Heterozygous TREM2 mutations in frontotemporal dementia. Neurobiol Aging. 2014 Apr;35(4):934.e7-10. Epub 2013 Oct 16 PubMed.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. Miyashita A, Wen Y, Kitamura N, Matsubara E, Kawarabayashi T, Shoji M, Tomita N, Furukawa K, Arai H, Asada T, Harigaya Y, Ikeda M, Amari M, Hanyu H, Higuchi S, Nishizawa M, Suga M, Kawase Y, Akatsu H, Imagawa M, Hamaguchi T, Yamada M, Morihara T, Takeda M, Takao T, Nakata K, Sasaki K, Watanabe K, Nakashima K, Urakami K, Ooya T, Takahashi M, Yuzuriha T, Serikawa K, Yoshimoto S, Nakagawa R, Saito Y, Hatsuta H, Murayama S, Kakita A, Takahashi H, Yamaguchi H, Akazawa K, Kanazawa I, Ihara Y, Ikeuchi T, Kuwano R. Lack of genetic association between TREM2 and late-onset Alzheimer's disease in a Japanese population. J Alzheimers Dis. 2014;41(4):1031-8. PubMed.
10. Tan T, Song Z, Yuan L, Xiong W, Deng X, Ni B, Chen Y, Deng H. Genetic analysis of TREM2 variants in Chinese Han patients with sporadic Parkinson's disease. Neurosci Lett. 2016 Jan 26;612:189-192. Epub 2015 Dec 15 PubMed.
11. Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, Brett TJ. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. Elife. 2016 Dec 20;5 PubMed.

Other Citations

1. L211P

Further Reading