Nasu–Hakola disease with a splicing mutation of TREM2 in a Japanese family
Article first published online: 22 DEC 2010
© 2010 The Author(s). European Journal of Neurology © 2010 EFNS
European Journal of Neurology
Volume 18, Issue 9, pages 1179–1183, September 2011
How to Cite
Numasawa, Y., Yamaura, C., Ishihara, S., Shintani, S., Yamazaki, M., Tabunoki, H. and Satoh, J.-I. (2011), Nasu–Hakola disease with a splicing mutation of TREM2 in a Japanese family. European Journal of Neurology, 18: 1179–1183. doi: 10.1111/j.1468-1331.2010.03311.x
- Issue published online: 11 AUG 2011
- Article first published online: 22 DEC 2010
- Received 28 September 2010 Accepted 18 November 2010
- exon 3 skipping;
- Nasu–Hakola disease;
- TREM2 mutation
Background: Nasu–Hakola disease (NHD) is a rare autosomal recessive disorder, characterized by a combination of progressive presenile dementia and formation of multifocal bone cysts, caused by genetic mutations of DAP12 and TREM2, which constitute a receptor/adapter signaling complex expressed on osteoclasts, dendritic cells, macrophages, and microglia. No Japanese patients with TREM2 mutations have been reported previously.
Methods: We reported three siblings affected with NHD in a Japanese family. Amongst them, two died of NHD during the fourth decade of life. The analysis of genomic DNA, cDNA cloning, and western blot of lymphocyte proteins was performed on samples of the living patient. The transcriptome was studied in the autopsied brain of one patient.
Results: We identified a homozygous conversion of a single nucleotide T to C at the second position of intron 3 in the splice-donor consensus site (c.482+2T>C) of the TREM2 gene, resulting in exon 3 skipping and aberrant expression of truncated proteins. We identified 136 upregulated genes involved in inflammatory response and immune cell trafficking and 188 downregulated genes including a battery of GABA receptor subunits and synaptic proteins in the patient’s brain.
Conclusions: This is the first report of a Japanese NHD family caused by a splicing mutation of TREM2 that induces both neuroinflammation and neurodegeneration.