Overview

Pathogenicity: Alzheimer's Disease : Benign, Frontotemporal Dementia : Unclear Pathogenicity
Clinical Phenotype: Primary Progressive Aphasia (Logopenic Variant)
Position: (GRCh38/hg38):Chr6:41159867 G>A
Position: (GRCh37/hg19):Chr6:41127605 G>A
dbSNP ID: rs149622783
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGG to CAG
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 3

Findings

In three studies of Caucasian cohorts, the R136Q variant was found in one of 281 AD patients and one of 501 controls (odds ratio 1.8, p = 1) (Guerreiro et al., 2013), one of 2047 AD patients and none of 1623 controls (p = 1) (Jin et al., 2014), and in none of 31 AD patients and one of 245 controls (Sirkis et al., 2016).  Subsequently, the variant was not associated with AD in a case-control study of almost 34,000 Caucasian subjects (approximately 18,000 AD and 16,000 controls; odds ratio: 1.66, p = 0.46) (Sims et al., 2017).

The R136Q variant was also found in a patient affected with logopenic variant primary progressive aphasia (Sirkis et al., 2016).

Neuropathology

No data.

Biological Effect

The arginine-to-glutamine substitution at amino acid 136 was predicted to be benign by PolyPhen2, (Guerreiro et al., 2013; Jin et al., 2014).  When heterologously expressed in HEK293 cells, the R136Q variant showed normal protein maturation, although immature forms of R136Q TREM2 migrated somewhat more slowly on SDS-PAGE than did immature forms of wild-type TREM2; in addition, the R136Q variant showed slightly reduced cell-surface expression compared with wild-type (Sirkis et al., 2016).

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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. 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.
3. 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.
4. 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Further Reading

No Available Further Reading