Mutations in TREM2 lead to pure early-onset dementia without bone cysts

Hum Mutat. 2008 Sep;29(9):E194-204. doi: 10.1002/humu.20836.


A genome-wide screen using 382 STR markers to localize and identify the gene implicated in early-onset dementia (EOD) without bone cysts in a Lebanese family with three affected subjects was conducted. A unique locus homozygous by descent at chromosome 6p21.2 locus was identified. Candidate genes were explored by fluorescent sequencing and the effect of the identified mutation was confirmed by qualitative and quantitative RT-PCR. The genetic analysis revealed a novel deletion, c.40+3delAGG, in the 5' consensus donor splice site in intron 1 of TREM2 gene which is known to be responsible for PLOSL (Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy) also designated as Nasu-Hakola disease. In silico analysis predicted a lower strength for the novel donor splice site. Qualitative RT-PCR revealed normal transcript while quantitative RT-PCR showed over twofold down-regulation of TREM2 transcripts. The expression profile of six genes SPP1, NEDD9, FSCN, BCL3, NFKBIA and CCL2 known as disrupted in TREM2-deficient samples was studied and showed same expression profile as TREM2-mutated samples except for CCL2 which was normally regulated. The significantly-reduced expression of TREM2 in our patients and the expression profiles of the six studied genes confirm a role for TREM2 in this distinct phenotype of EOD without bone cysts. To our knowledge, this is the first report of mutations in TREM2 causing a pure dementia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Aged
  • Alternative Splicing
  • Bone Cysts / genetics*
  • DNA Mutational Analysis
  • Dementia / genetics*
  • Family Health
  • Female
  • Haplotypes
  • Homozygote
  • Humans
  • Male
  • Membrane Glycoproteins / genetics*
  • Middle Aged
  • Mutation*
  • Pedigree
  • Phenotype
  • Receptors, Immunologic / genetics*


  • Membrane Glycoproteins
  • Receptors, Immunologic
  • TREM2 protein, human