Overview

Pathogenicity: Nasu-Hakola Disease : Pathogenic
Clinical Phenotype: Nasu-Hakola Disease
Reference Assembly: GRCh37/hg19
Position: Chr6:41129015 T>G
dbSNP ID: rs121908402
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to GGG
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 2

Findings

The rs121908402 variant introduces a valine-to-glycine substitution at amino acid 126. This variant, in a homozygous state, was found in two unrelated patients with Nasu-Hakola disease (also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy) (Klunemann et al., 2005), 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).

Neuropathology

Neuropathological characterization of NHD patients carrying the V126G variant is currently lacking. However, imaging revealed typical findings for patients with NHD, including leukoencephalopathy with sparing of arcuate fibers, cerebral atrophy, and thinning of the corpus callosum (Klunemann et al., 2005).

Biological Effect

Compared with wild-type TREM2, the V126G variant elutes earlier from size-exclusion chromatography columns and forms SDS-resistant aggregates detectable by western blotting, suggesting protein misfolding (Kober et al., 2017). This variant has poor cell-surface expression and is defective for N-linked glycosylation in the Golgi, but it appears to be subject to an alternative, O-linked glycosylation pathway (Sirkis et al., 2017).

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References

Paper Citations

1. Klünemann HH, Ridha BH, Magy L, Wherrett JR, Hemelsoet DM, Keen RW, De Bleecker JL, Rossor MN, Marienhagen J, Klein HE, Peltonen L, Paloneva J. The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology. 2005 May 10;64(9):1502-7. 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. Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, Brett TJ. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. Elife. 2016 Dec 20;5 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.

Further Reading

No Available Further Reading