Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Reference Assembly: GRCh37/hg19
Position: Chr6:41129188 C>G
dbSNP ID: rs753372932
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAC to AAG
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 2

Findings

In a Caucasian cohort, the N68K variant was found in one of 1105 cognitively healthy controls and in none of 1090 Alzheimer’s patients (Guerreiro et al., 2013). The variant was not found in a Japanese study that included approximately 2200 Alzheimer’s patients and 2500 controls (Miyashita et al., 2014).

Neuropathology

No data.

Biological Effect

The asparagine-to-lysine substitution at amino acid 68 was predicted by PolyPhen2 to be benign (Guerreiro et al., 2013). Biochemical observations suggest that the variant does not drastically alter protein folding or promote aggregation (Kober et al., 2017).

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References

Paper Citations

1. 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.
2. 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.
3. 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.

Further Reading

No Available Further Reading