title: Nasu-Hakola disease with a splicing mutation of TREM2 in a Japanese family.
abstract: 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.
authors.affiliation: Department of Neurology, Toride Kyodo General Hospital, Toride City, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Numasawa
authors.forename: C
authors.initials: C
authors.lastname: Yamaura
authors.forename: S
authors.initials: S
authors.lastname: Ishihara
authors.forename: S
authors.initials: S
authors.lastname: Shintani
authors.forename: M
authors.initials: M
authors.lastname: Yamazaki
authors.forename: H
authors.initials: H
authors.lastname: Tabunoki
authors.forename: J-I
authors.initials: JI
authors.lastname: Satoh
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics*; D015153:Blotting, Western; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D006801:Humans; D008060:Lipodystrophy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D017354:Point Mutation; D011971:Receptors, Immunologic / Q000235:genetics*; D013344:Subacute Sclerosing Panencephalitis / Q000235:genetics* / Q000473:pathology
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human