Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Position: (GRCh38/hg38):Chr6:41159868 C>T
Position: (GRCh37/hg19):Chr6:41127606 C>T
dbSNP ID: rs772641807
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGG to TGG
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 3

Findings

In two studies of Caucasian subjects, the R136W variant was found in two of 2003 AD patients and none of 1562 controls (Jin et al., 2014) and in none of 31 AD patients and one of 245 controls (Sirkis, et al., 2016,).

Neuropathology

No data.

Biological Effect

When heterologously expressed in HEK 293 cells, the R136W variant exhibited normal protein maturation but a reduction in total and cell-surface expression compared with wild-type TREM2 (Sirkis, et al., 2016).  However, when stimulated by purified phospholipids, reporter cells expressing the R136W variant responded similarly to cells expressing wild-type TREM2 (Song et al., 2017).

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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. 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.

Further Reading

No Available Further Reading