Overview

Pathogenicity: Nasu-Hakola Disease : Pathogenic, Frontotemporal Dementia : Unclear Pathogenicity
Clinical Phenotype: Frontotemporal Dementia, Nasu-Hakola Disease
Position: (GRCh38/hg38):Chr6:41159873 A>G
Position: (GRCh37/hg19):Chr6:41127611 A>G
dbSNP ID: rs28939079
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAT to GGT
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 3

Findings

The rs28939079 variant introduces an aspartate-to-glycine substitution at amino acid 134. This variant, in a homozygous state, was found in an American patient of Slovakian descent, who was affected by Nasu-Hakola disease (also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy) (Paloneva et al., 2002), a rare, autosomal-recessive disease characterized by bone fractures and a frontotemporal dementia (FTD)-like syndrome beginning in the fourth decade of life (Paloneva et al., 2002). This variant was not found in 100 Caucasian controls (Paloneva et al., 2002).

In addition, a patient presenting with an early-onset FTD-like syndrome and chorea was found to be a compound heterozygote, carrying both the D134G and c.482+2 T>C mutant alleles (Redaelli et al., 2018). Symptoms appeared at age 30, in the form of apathy, depression and chorea, followed by behavioral disturbances two years later, and cognitive impairment seven years after symptom onset; the patient was in a vegetative state at age 59, having been bed-ridden for twelve years. There were no reports of bone fractures. A brother received a diagnosis of FTD at age 42, but DNA was not available for sequencing.

Neuropathology

Brain atrophy was reported in the NHD patient homozygous for this mutation; whether this finding was from autopsy or imaging was not specified (Paloneva et al., 2002).

In the FTD patient with the compound heterozygous mutation, MRI at age 37 revealed white matter abnormalities in the frontal lobes with ventricular enlargement, and SPECT showed hypoperfusion of the frontal and parietal lobes (Redaelli et al., 2018).

Biological Effect

The D134G variant appears to undergo normal protein maturation, and its cell-surface expression is comparable to that of wild-type TREM2 (Sirkis et al., 2017).

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References

Paper Citations

1. Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R, Bianchin M, Bird T, Miranda R, Salmaggi A, Tranebjaerg L, Konttinen Y, Peltonen L. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet. 2002 Sep;71(3):656-62. Epub 2002 Jun 21 PubMed.
2. Paloneva J, Autti T, Hakola P, Haltia MJ. Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL). In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens K, Amemiya A, Ledbetter N, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. 2002 Jan 24 [updated 2015 Mar 12].
3. Redaelli V, Salsano E, Colleoni L, Corbetta P, Tringali G, Del Sole A, Giaccone G, Rossi G. Frontotemporal Dementia and Chorea Associated with a Compound Heterozygous TREM2 Mutation. J Alzheimers Dis. 2018;63(1):195-201. PubMed.
4. 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. c.482+2 T>C

Further Reading