Overview

Pathogenicity: Nasu-Hakola Disease : Pathogenic, Frontotemporal Dementia : Unclear Pathogenicity
Clinical Phenotype: Frontotemporal Dementia, Nasu-Hakola Disease
Position: (GRCh38/hg38):Chr6:41159790 T>C
Position: (GRCh37/hg19):Chr6:41127528 T>C
dbSNP ID: rs386834144
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Deletion
Genomic Region: Intron 3

Findings

The rs386834144 variant substitutes a cytosine for a thymine in the splice-donor consensus site at the second position of intron 3 (482+2T>C), resulting in exon 3 skipping. This homozygous variant was first identified in two Italian patients with Nasu-Hakola disease; their two unaffected siblings were homozygous for the common allele (Paloneva et al., 2002). Subsequently, this variant was also found in a Japanese family affected by Nasu-Hakola disease (Numasawa et al., 2011). The 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 c.482+2T>C and D134G mutant alleles, in trans (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 Italian NHD patients homozygous for this mutation; whether this finding was from autopsy or imaging was not specified (Paloneva et al., 2002). In a Japanese NHD patient, imaging revealed atrophy of the frontotemporal cortex and dilatation of the lateral ventricle (MRI), basal ganglia calcification (CT), and hypoperfusion in the frontotemporal cortex (SPECT) (Numasawa et al., 2011).

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 biochemical consequences of the rs386834144 variant were examined using cDNA and protein prepared from peripheral blood monocytes from a Japanese NHD patient (Numasawa et al., 2011). Cloning and sequencing of the TREM2 open reading frame confirmed exon 3 skipping, with deletion of exons 2 and/or 4, and the presence of premature or original stop codons. Two truncated TREM2 protein products were detected by western blot. Sequence analysis indicated that the truncated proteins are likely to be nonfunctional.

Gene expression analysis of frontal lobe tissue from a deceased Japanese NHD patient homozygous for the rs386834144 variant revealed upregulation of microglial markers and downregulation of transcripts for GABA receptor sub-units and synaptic proteins (Numasawa et al., 2011).

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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. Numasawa Y, Yamaura C, Ishihara S, Shintani S, Yamazaki M, Tabunoki H, Satoh JI. Nasu-Hakola disease with a splicing mutation of TREM2 in a Japanese family. Eur J Neurol. 2011 Sep;18(9):1179-83. PubMed.
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.

Other Citations

1. D134G

Further Reading

No Available Further Reading