Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity, Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Behavioral variant FTD
Position: (GRCh38/hg38):Chr6:41161515 C>T
Position: (GRCh37/hg19):Chr6:41129253 C>T
dbSNP ID: rs753325601
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to TGC
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 2

Findings

The R47C variant was found in one Alzheimer’s patient in a Caucasian cohort from the Alzheimer’s Disease Sequencing Project (2927 AD, 2633 cognitively healthy controls) (Sirkis et al., 2016).

A woman of South Asian ancestry suffering from behavioral variant FTD was found to be a homozygous carrier of the R47C variant (Ng et al., 2018). MRI showed symmetric frontal and temporal lobe atrophy, consistent with the clinical diagnosis of FTD.  Cerebrospinal fluid biomarkers (Aβ42, total tau, and phospho-tau) were inconsistent with AD. DNA from family members was not available, precluding segregation analysis. No homozygous carriers of the R47C variant were found in either the ExAC or gnomAD databases.

Neuropathology

Unknown, but MRI showed symmetric frontal and temporal lobe atrophy in homozygous carrier.

Biological Effect

The R47C variant exhibited normal maturation but decreased total and cell-surface expression when heterologously expressed in HEK293 cells (Sirkis et al., 2016).

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References

Paper Citations

1. 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.
2. Ng AS, Tan YJ, Yi Z, Tandiono M, Chew E, Dominguez J, Macas M, Ng E, Hameed S, Ting S, Tan EK, Foo JN, Kandiah N. Targeted exome sequencing reveals homozygous TREM2 R47C mutation presenting with behavioral variant frontotemporal dementia without bone involvement. Neurobiol Aging. 2018 Aug;68:160.e15-160.e19. Epub 2018 Apr 16 PubMed.

Further Reading

No Available Further Reading