Overview

Pathogenicity: Nasu-Hakola Disease : Pathogenic
Clinical Phenotype: Nasu-Hakola Disease
Position: (GRCh38/hg38):Chr6:41161504 G>T
Position: (GRCh37/hg19):Chr6:41129242 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAG to TAG
Reference Isoform: TREM2 Isoform 1 (230 aa)
Genomic Region: Exon 2

Findings

The W50C variant, in a homozygous state, was found in a Greek patient affected by Nasu-Hakola disease (NHD; also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy) (Dardiotis et al., 2017), a rare autosomal-recessive disease characterized by bone cysts and early onset frontotemporal dementia (FTD) (Paloneva et al., 2002). The patient exhibited personality changes at age 30, followed by behavioral changes suggestive of frontal lobe dysfunction, and cognitive decline.

The patient's parents and brother were heterozygous carriers of the variant. The W50C variant was not found in 200 control subjects (Dardiotis et al., 2017).

Neuropathology

Neuropathological characterization of individuals carrying the W50C variant is currently lacking. However, MRI of the NHD patient homozygous for this mutation revealed brain atrophy, diffuse white-matter hyperintensities, and thinning of the corpus callosum; CT showed basal ganglia calcification (Dardiotis et al., 2017).

Biological Effect

The tryptophan-to-cysteine substitution was predicted to be harmful by two in silico prediction tools, Polyphen-2 and SIFT (Dardiotis et al., 2017). Peripheral blood cells derived from the patient did not differ from those of her parents or two healthy control subjects in terms of phagocytic activity or respiratory bursts (Dardiotis et al., 2017).

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References

Paper Citations

1. Dardiotis E, Siokas V, Pantazi E, Dardioti M, Rikos D, Xiromerisiou G, Markou A, Papadimitriou D, Speletas M, Hadjigeorgiou GM. A novel mutation in TREM2 gene causing Nasu-Hakola disease and review of the literature. Neurobiol Aging. 2017 May;53:194.e13-194.e22. Epub 2017 Jan 20 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].

Further Reading

No Available Further Reading