Mutations

TREM2 T66M

Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Behavioral variant FTD
Reference Assembly: GRCh37 (105)
Position: Chr6:41129195 C>T
dbSNP ID: rs201258663
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: ACG to ATG
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 2
Research Models: 1

Findings

The homozygous T66M variant was first described in a Turkish man, the son of consanguineous parents, who developed aggressive and perseverative behavioral changes in his 30s, followed by cognitive impairment in his 40s (Guerreiro et al., 2013). An MRI at the age of 45 revealed frontal lobe atrophy, ventricular enlargement, and white-matter abnormalities. Neurological signs included bradykinesia, apraxia, and postural instability. Frontal lobe atrophy and behavioral and cognitive impairment progressively worsened. This homozygous variant was subsequently found in two siblings from a consanguineous Italian family with autosomal-recessive early onset behavioral variant FTD (LaBer et al., 2014). Atypical signs in this family included early parietal and hippocampal atrophy (in addition to pronounced frontal lobe atrophy), parkinsonism, and epilepsy.

It is unclear whether this variant is pathogenic when heterozygous. An unaffected brother of the Turkish patient described above was found to be a heterozygous carrier of this variant, and another heterozygous carrier was found in a cohort of 351 healthy controls (Guerreiro et al., 2013). However, a German patient with behavioral variant FTD was found to be heterozygous for this variant (Thelen et al., 2014). In a case-control study of 352 Italian FTD patients and 484 controls, the T66M variant was found in one heterozygous patient and in none of the controls (p = 0.24) (Borroni et al., 2014).

The T66M variant was not associated with Alzheimer’s disease in three cohorts of European-American descent (Borroni et al., 2014; Guerreiro et al., 2013; Jin et al., 2014). The variant was not found in Japanese subjects (approximately 2,200 cases and 2,500 controls) (Miyashita et al., 2014).

The limited data available to date suggest that individuals carrying the T66M variant have greatly decreased levels of soluble TREM2 (sTREM2) in cerebrospinal fluid (Henjum et al., 2016; Kleinberger et al., 2014; Piccio et al., 2016).

Neuropathology

Unknown. MRI revealed frontal lobe atrophy, ventricular enlargement, and white-matter abnormalities in one homozygous carrier, and frontal and parietal lobe atrophy in an additional two (sibling) homozygous carriers.

Biological Effect

The threonine-to-methionine substitution at amino acid 66 appears to result in protein misfolding, impaired maturation and trafficking of TREM2, and reduced ligand binding.

X-ray crystallography revealed that amino acid 66 is buried inside the folded TREM2 protein, leading to the hypothesis that the T66M mutation disrupts protein folding (Kober et al., 2016). This hypothesis is supported by the observations that the T66M variant exhibited decreased detergent solubility compared with the wild-type protein (Park et al., 2015), specific anti-TREM2 antibodies did not recognize T66M TREM2 expressed by HEK293F cells, and the variant protein formed aggregates while the wild-type protein remained monomeric (Kober et al., 2016).

Unlike wild-type TREM2, which is glycosylated in the Golgi apparatus and then transported to the cell surface, the T66M variant accumulates in the endoplasmic reticulum, resulting in greatly decreased cell-surface localization and decreased shedding of sTREM2 (Kleinberger et al., 2014; Park et al., 2015; Sirkis et al., 2017; Song et al., 2017; Varnum et al., 2017). Although the T66M variant is defective for N-linked glycosylation in the Golgi, it appears to be subject to an alternative, O-linked glycosylation pathway (Park et al., 2015; Sirkis et al., 2017). In a novel split-luciferase assay designed to monitor TREM2-DAP12/TYROBP coupling, HEK293 cells expressing the T66M variant generated a ligand-independent signal, suggesting constitutive (intracellular) coupling of this variant and DAP12/TYROBP (Varnum et al., 2017).

In a cell-free assay, the T66M 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 T66M variant showed reduced uptake of lipoproteins (Yeh et al., 2016) and less phagocytic activity toward fluorescent latex beads, E. coli conjugated to pHrodo, and aggregated Aβ42 (Kleinberger et al., 2014).

Research Models

The effects of the T66M variant have been studied in vivo in a knock-in mouse created using CRISPR/Cas9 genome editing (Kleinberger et al., 2017). The mutation did not affect levels of mRNA. Consistent with the in vitro results, these mice exhibited a gene-dose-dependent accumulation of immature TREM2 and reduction of sTREM2 in brain, CSF, and serum. In vivo imaging revealed reduced microglial activity (small-animal positron emission tomography (µPET) for the 18-kD translocator protein ligand), reduced brain glucose metabolism (fluoro-2-deoxy- D-glucose µPET), and reduced cerebral blood flow (continuous arterial spin-labeled magnetic resonance imaging) in T66M mice compared with wild-type mice. In addition, T66M knock-in mice showed an exaggerated and/or prolonged inflammatory response to lipopolysaccharide injection. The age-dependent accumulation of clusters of Iba1-immunoreactive microglia seen in wild-type mice was not seen in T66M knock-in mice.

Last Updated: 07 Feb 2018

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References

Paper Citations

  1. . The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J. 2017 Jul 3;36(13):1837-1853. Epub 2017 May 30 PubMed.
  2. . 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.
  3. . Homozygous TREM2 mutation in a family with atypical frontotemporal dementia. Neurobiol Aging. 2014 Oct;35(10):2419.e23-2419.e25. Epub 2014 Apr 18 PubMed.
  4. . Investigation of the role of rare TREM2 variants in frontotemporal dementia subtypes. Neurobiol Aging. 2014 Nov;35(11):2657.e13-2657.e19. Epub 2014 Jun 20 PubMed.
  5. . Heterozygous TREM2 mutations in frontotemporal dementia. Neurobiol Aging. 2014 Apr;35(4):934.e7-10. Epub 2013 Oct 16 PubMed.
  6. . TREM2 variants in Alzheimer's disease. N Engl J Med. 2013 Jan 10;368(2):117-27. Epub 2012 Nov 14 PubMed.
  7. . 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.
  8. . 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.
  9. . Cerebrospinal fluid soluble TREM2 in aging and Alzheimer's disease. Alzheimers Res Ther. 2016 Apr 27;8(1):17. PubMed.
  10. . TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med. 2014 Jul 2;6(243):243ra86. PubMed.
  11. . Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 2016 Jun;131(6):925-33. Epub 2016 Jan 11 PubMed.
  12. . Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. Elife. 2016 Dec 20;5 PubMed.
  13. . 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.
  14. . 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.
  15. . 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.
  16. . A split-luciferase complementation, real-time reporting assay enables monitoring of the disease-associated transmembrane protein TREM2 in live cells. J Biol Chem. 2017 Jun 23;292(25):10651-10663. Epub 2017 May 10 PubMed.
  17. . 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.

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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