Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Reference Assembly: GRCh37/hg19
Position: Chr6:41129279 A>G
dbSNP ID: rs797044603
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TAT to TGT
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 2
Research Models: 1


The rs797044603 variant results in a tyrosine-to-cysteine substitution at amino acid 38 (Y38C). This variant, in a homozygous state, was found in a Turkish man who developed seizures and an FTD-like syndrome in his fourth decade, with death occurring 12 years after symptom onset. Magnetic resonance imaging (MRI) revealed global cortical atrophy that was especially prominent in the frontal lobes, thinning of the corpus callosum, periventricular white-matter abnormalities, and ventricular enlargement (Guerreiro et al., 2013), similar to what is seen in patients with Nasu-Hakola disease (NHD). However, this patient did not show evidence of basal ganglia calcification, commonly seen in NHD, nor did he show any evidence of the bone involvement characteristic of NHD.

In addition, two Turkish sisters presenting with an FTD-like syndrome were found to be compound heterozygotes, carrying both the Y38C and D86V mutant alleles (Guerreiro et al., 2013). MRI of the proband revealed similar features to those described above, as well as probable calcification in the globus pallidus. Bone abnormalities were absent. The patients' father (Y38C carrier), mother (D86V carrier), and brother (Y38C carrier) were unaffected.

An association with Alzheimer’s disease has not been established for theY38C variant. In a cohort of European descent, this variant found in three of 1,091 AD cases and none of 1,107 controls (p = 0.12) (Guerreiro et al., 2013). The variant was not found in Japanese subjects (approximately 2,200 cases and 2,500 controls) (Miyashita et al., 2014).


Unknown. MRI has revealed cortical atrophy and white matter abnormalities in carriers of the Y38C variant.

Biological Effect

The tyrosine-to-cysteine substitution at amino acid 38 alters post-translational processing of TREM2, ligand binding, and TREM2-mediated phagocytosis.

Unlike wild-type TREM2, which is glycosylated in the Golgi apparatus and then transported to the cell surface, the Y38C variant accumulates in the endoplasmic reticulum (ER), resulting in greatly reduced cell-surface localization and reduced shedding of soluble TREM2 (sTREM2) (Kleinberger et al., 2014; Park et al., 2015; Sirkis et al., 2017. Retention of Y38C TREM2 in the ER could occur if the protein is misfolded, and there is some evidence for misfolding—compared with wild-type TREM2, the Y38C variant exhibits decreased detergent solubility (Park et al., 2015), elutes earlier from size-exclusion chromatography columns, and forms SDS-resistant aggregates (Kober et al., 2017). However, there is also evidence that the Y38C variant is not grossly misfolded and is actually exported from the ER to an early Golgi compartment, but is then returned to the ER via the coat protein complex I pathway as means of protein quality control (Sirkis et al., 2017). The Y38C variant is defective for N-linked glycosylation in the Golgi, but it appears to be subject to an alternative, O-linked glycosylation pathway (Park et al., 2015; Sirkis et al., 2017).

In a cell-free assay, the Y38C variant failed to bind LDL, lipidated clusterin, or lipidated APOE—all of which bound wild-type TREM2 (Yeh et al., 2016). Compared with cells expressing wild-type TREM2, HEK293 cells expressing the Y38C variant showed reduced phagocytosis of lipoproteins (Yeh et al., 2016), fluorescent latex beads, E. coli conjugated to pHrodo, and aggregated Aβ42 (Kleinberger et al., 2014, 24990881). BV2 microglial cells transfected with Y38C TREM2 also showed less uptake of aggregated Aβ than did cells transfected with wild-type TREM2 (Kleinberger et al., 2014). Finally, the Y38C variant is less able to sustain signaling upon ligand binding (Kober et al., 2017): Cos-7 cells co-transfected with FLAG-tagged wild-type TREM2 and DAP12 showed elevated levels of p-ERK for at least 30 minutes after stimulation with an anti-FLAG antibody, while cells co-expressing the Y38C variant and DAP12 showed elevated pERK at 10 minutes, but not 30 minutes, post-stimulation. A similar result was found using RAW264.7 macrophages.

Last Updated: 07 Feb 2018


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Paper Citations

  1. . Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol. 2013 Jan;70(1):78-84. PubMed.
  2. . Novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family. Neurobiol Aging. 2013 Dec;34(12):2890.e1-5. Epub 2013 Jul 17 PubMed.
  3. . TREM2 variants in Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):117-27. Epub 2012 Nov 14 PubMed.
  4. . 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.
  5. . TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med. 2014 Jul 2;6(243):243ra86. PubMed.
  6. . Disease-Associated Mutations of TREM2 Alter the Processing of N-Linked Oligosaccharides in the Golgi Apparatus. Traffic. 2015 May;16(5):510-8. Epub 2015 Feb 24 PubMed.
  7. . Neurodegeneration-associated mutant TREM2 proteins abortively cycle between the ER and ER-Golgi intermediate compartment. Mol Biol Cell. 2017 Oct 1;28(20):2723-2733. Epub 2017 Aug 2 PubMed.
  8. . Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. Elife. 2016 Dec 20;5 PubMed.
  9. . TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron. 2016 Jul 20;91(2):328-40. PubMed.

Other Citations

  1. D86V

Further Reading

Protein Diagram

Primary Papers

  1. . Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol. 2013 Jan;70(1):78-84. PubMed.


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