Overview

Pathogenicity: Frontotemporal Dementia : Unclear Pathogenicity
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr6:41161397 A>T
Position: (GRCh37/hg19):Chr6:41129135 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAC to GTC
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 2

Findings

Two Turkish sisters presenting with an FTD-like syndrome and seizures were found to be compound heterozygotes, carrying both the Y38C and D86V variants (Guerreiro et al., 2013). Their mother was a heterozygous carrier of the D86V variant, as was a healthy control in a Turkish cohort previously screened for mutations in TREM2 exon 2 (Guerreiro et al., 2013).

Neuropathology

Unknown. MRI of the proband revealed cortical atrophy that was especially prominent in the frontal, lateral temporal, and parietal lobes; thinning of the corpus callosum; periventricular white-matter abnormalities; ventricular enlargement; and probable calcification in the globus pallidus, similar to what is seen in Nasu-Hakola disease. However, the patient did not show any evidence of bone involvement (Guerreiro et al., 2013).

Biological Effect

The aspartate-to-valine substitution in TREM2 impairs protein maturation and results in decreased cell-surface expression. This variant is apparently unable to undergo complex N-linked glycosylation, but alternatively may undergo O-linked glycosylation (Sirkis et al., 2017).

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References

Paper Citations

1. Guerreiro R, Bilgic B, Guven G, Brás J, Rohrer J, Lohmann E, Hanagasi H, Gurvit H, Emre M. 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.
2. Guerreiro RJ, Lohmann E, Brás JM, Gibbs JR, Rohrer JD, Gurunlian N, Dursun B, Bilgic B, Hanagasi H, Gurvit H, Emre M, Singleton A, Hardy J. 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. Sirkis DW, Aparicio RE, Schekman R. 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.

Other Citations

1. Y38C

Further Reading

No Available Further Reading