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TREM2 (27)

TREM2 encodes Triggering Receptor Expressed on Myeloid Cells 2, a transmembrane receptor that modulates microglial activity and survival. TREM2 variants cause Nasu-Hakola disease (NHD), a rare autosomal recessive early-onset dementia, and may modify the risk of developing Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).​

Mutation Clinical
Phenotype
Pathogenicity Neuropathology Biological Effect Genomic Position Genomic Region Mutation Type
Codon Change
Research
Models
Primary
Papers
E14X
Nasu-Hakola Disease NHD : Pathogenic Unknown. Premature truncation codon; no transcripts detected.

rs386834143
Coding
Exon 1
Point, Nonsense
GAG to TAG
0 Paloneva et al., 2003
Q33X
Alzheimer's Disease, Frontotemporal Dementia, Nasu-Hakola Disease NHD : Pathogenic, FTD : Pathogenic, AD : Possible Risk Modifier Unknown for homozygous carriers; MRI showed cerebral atrophy. Heterozygous AD patient showed typical AD pathology. Loss of TREM2 expression.

rs104894002
Coding
Exon 2
Point, Nonsense
CAG to TAG
0 Soragna et al., 2003;
Guerreiro et al., 2013
Y38C
Frontotemporal Dementia FTD : Pathogenic Unknown; MRI shows cortical atrophy and white matter abnormalities. Alters post-translational processing of TREM2, ligand binding, and TREM2-mediated phagocytosis.

rs797044603
Coding
Exon 2
Point, Missense
TAT to TGT
1 Guerreiro et al., 2013
W44X
Nasu-Hakola Disease NHD : Pathogenic Brain atrophy reported. Predicted to result in truncated protein lacking transmembrane and cytoplasmic domains.

rs104894001
Coding
Exon 2
Point, Nonsense
TGG to TGA
0 Paloneva et al., 2002
R47H
Alzheimer's Disease, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, Parkinson's Disease AD : Risk Modifier, FTD : Possible Risk Modifier, PD : Possible Risk Modifier, ALS : Possible Risk Modifier AD patients heterozygous for the R47H variant:  generally typical AD pathology, but subtle differences compared to non-carriers, including decreased microglial coverage of amyloid plaques and accumulation of phagosomes in microglia. Decreased ligand binding to TREM2 and impaired TREM2-mediated activation.

rs75932628
Coding
Exon 2
Point, Missense
CGC to CAC
2 Guerreiro et al., 2013;
Jonsson et al., 2013
W50C
Nasu-Hakola Disease NHD : Pathogenic Unknown; imaging showed brain atrophy, diffuse white-matter hyperintensities, thinning of the corpus callosum, and basal ganglia calcification. Unknown; predicted to be harmful in silico by Polyphen-2 and SIFT.

Coding
Exon 2
Point, Missense
GAG to TAG
0 Dardiotis et al., 2017
R62H
Alzheimer's Disease AD : Risk Modifier AD patients heterozygous for the R62H variant: decreased microglial coverage of amyloid plaques and increased accumulation of phagosomes in microglia, compared to non-carriers. Decreased ligand binding to TREM2 and impaired TREM2-mediated activation.

rs143332484
Coding
Exon 2
Point, Missense
CGT to CAT
0 Jin et al., 2014;
Sims et al., 2017
T66M
Behavioral variant FTD FTD : Pathogenic Unknown; MRI showed frontal lobe atrophy, ventricular enlargement, and white-matter abnormalities in one homozygous carrier, and frontal and parietal lobe atrophy in two other homozygous carriers. Greatly decreased cell-surface expression and shedding of sTREM2, reduced ligand binding, and impaired phagocytosis.

rs201258663
Coding
Exon 2
Point, Missense
ACG to ATG
1 Guerreiro et al., 2013
W78X
Nasu-Hakola Disease NHD : Pathogenic Brain atrophy has been reported. Predicted to result in truncated protein lacking transmembrane and cytoplasmic domains.

rs104893998
Coding
Exon 2
Point, Nonsense
TGG to TAG
0 Paloneva et al., 2002
D86V
Frontotemporal Dementia FTD : Unclear Pathogenicity Unknown; MRI of a patient carrying both the Y38C and D86V variants, showed cortical atrophy, thinning of the corpus callosum, periventricular white-matter abnormalities,ventricular enlargement and probable globus pallidus calcification. Decreased cell-surface expression and defective N-linked glycosylation.

Coding
Exon 2
Point, Missense
GAC to GTC
0 Guerreiro et al., 2013
D87N
Alzheimer's Disease AD : Possible Risk Modifier Typical AD pathology in single described case (Braak Stage 6). Decreased binding to lipoproteins in cell-free assay, but increased ligand-stimulated activation in reporter cell line.

rs142232675
Coding
Exon 2
Point, Missense
GAT to AAT
0 Guerreiro et al., 2013
T96K
Frontotemporal Dementia FTD : Possible Risk Modifier Unknown; carriers of the T96K/W191X/L211P variants have lower levels of sTREM2 in CSF, compared with noncarriers. Increased binding to cell-derived ligands and increased activation by phospholipids seen in reporter cell line.

rs2234253
Coding
Exon 2
Point, Missense
ACG to AAG
0 Thelen et al., 2014
A105RfsX84
(TREM2 313delG)
Nasu-Hakola Disease NHD : Pathogenic Unknown; imaging showed cerebral atrophy, leukoencephalopathy, thinning of the corpus callosum, basal ganglia calcification. Unknown.

rs386834141
Coding
Exon 2
Deletion
GCG to CGG
0 Klünemann et al., 2005
V126G
Nasu-Hakola Disease NHD : Pathogenic Unknown; MRI showed leukoencephalopathy with sparing of arcuate fibers, cerebral atrophy, and thinning of the corpus callosum. Poor cell-surface expression and defective for N-linked glycosylation in the Golgi.

rs121908402
Coding
Exon 2
Point, Missense
GTG to GGG
0 Klünemann et al., 2005
D134G
Nasu-Hakola Disease NHD : Pathogenic Brain atrophy. Unknown.

rs28939079
Coding
Exon 3
Point, Missense
GAT to GGT
0 Paloneva et al., 2002
H157Y
Alzheimer's Disease AD : Possible Risk Modifier Unknown. Increases shedding of sTREM2. Reduces activation in response to phospholipid ligands and decreases phagocytosis.

rs2234255
Coding
Exon 3
Point, Missense
CAC to TAC
0 Jiang et al., 2016;
Jiang et al., 2016;
Sims et al., 2017
K186N
Nasu-Hakola Disease NHD : Pathogenic Brain atrophy. Predicted to result in defects in signal transduction.

 

 


rs28937876
Coding
Exon 4
Point, Missense
AAG to AAT
0 Paloneva et al., 2002
W191X
Alzheimer's Disease AD : Unclear Pathogenicity Unknown. Unknown.

rs2234258
Coding
Exon 4 of transcript variant 2
Point, Nonsense
TGG to TAG
0 Jin et al., 2015
W198X
Behavioral variant FTD FTD : Pathogenic Unknown; frontal lobe atrophy seen on MRI. Premature truncation.

Coding
Exon 4
Point, Nonsense
TGG to TGA
0 Giraldo et al., 2013
L211P
Alzheimer's Disease, Frontotemporal Dementia AD : Possible Risk Modifier, FTD : Possible Risk Modifier Unknown; lower levels of sTREM2 in CSF of T96K/W191X/L211P carriers. Predicted tolerated in silico by SIFT and benign by PolyPhen-2.

rs2234256
Coding
Exon 4
Point, Missense
CTG to CCG
0 Jin et al., 2015
G90VfsX99
(TREM2 269delG)
Nasu-Hakola Disease NHD : Pathogenic Unknown; MRI showed leukoencephalopathy and cerebral atrophy. Unknown.

rs386834140
Coding
Exon 2
Deletion
GGT to GTG
0 Klünemann et al., 2005
c.40+3 delAGG
Frontotemporal Dementia FTD : Pathogenic Unknown; MRI showed brain atrophy, including thinning of the corpus callosum. Reduction in the level of TREM2 transcripts.

Non-Coding
Intron 1
Deletion
0 Chouery et al., 2008
c.482+1 G>A
Progressive Nonfluent Aphasia FTD : Pathogenic Unknown; MRI showed periventricular white-matter hyperintensities, enlargement of the lateral ventricles, and thinning of the corpus callosum. Unknown.

Non-Coding
Intron 3
Point
0 Chee et al., 2017
c.482+2 T>C
Nasu-Hakola Disease NHD : Pathogenic Unknown; imaging showed brain atrophy, basal ganglia calcification, and hypoperfusion in the frontotemporal cortex. Exon 3 skipping, with deletion of exons 2 and/or 4, and the presence of premature or original stop codons; two truncated TREM2 protein products detected, which are likely to be nonfunctional.

rs386834144
Non-Coding
Intron 3
Point
0 Paloneva et al., 2002;
Numasawa et al., 2011
rs7748513
Alzheimer's Disease AD : Possible Risk Modifier Unknown. Unknown.

rs7748513
Non-Coding
Intron 2
Point
0 Reitz et al., 2013
rs7748777
Alzheimer's Disease, ~ 1 year follow-up AD : Possible Risk Modifier Unknown. Unknown.

rs7748777
Non-Coding
Upstream
Point
0 Wang et al., 2015
rs9357347
Alzheimer's Disease AD : Possible Risk Modifier Unknown. Predicted to influence transcription factor binding; 6 percent increase in expression of TREM2 and TREML1 in temporal cortex.

rs9357347
Non-Coding
Intergenic - TREM locus
Point
0 Carrasquillo et al., 2017