Overview

Pathogenicity: Nasu-Hakola Disease : Pathogenic
Clinical Phenotype: Nasu-Hakola Disease
Position: (GRCh38/hg38):Chr6:41158991 G>T
Position: (GRCh37/hg19):Chr6:41126729 G>T
dbSNP ID: rs28937876
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AAG to AAT
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 4

Findings

The rs28937876 variant introduces a lysine-to-asparagine substitution at amino acid 186. This variant, in a homozygous state, was found in two sisters from a Norwegian family who were 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). Two unaffected siblings of these sisters were heterozygous for this variant, and the variant was not found in 100 Caucasian controls (Paloneva et al., 2002).

Neuropathology

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

Biological Effect

The K168N variant appears to undergo normal protein maturation and exhibits high levels of cell-surface expression. The variant was predicted to result in defects in signal transduction due to loss of the conserved lysine residue, which mediates the interaction between TREM2 and the adaptor protein DAP12, but this prediction has not yet been tested experimentally (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. 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.

Further Reading

No Available Further Reading