Mutations inTREM2lead to pure early-onset dementia without bone cysts

Abstract

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.

Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells

“…In both models, peripheral, hematopoietic side effects are likely the main contributing factors of the lethal phenotype. Nevertheless, long-term elimination or dysfunction of microglia likely has deleterious consequences on CNS homeostasis as exemplified in neurodegenerative conditions, such as Nasu-Hakola disease or Rett syndrome (22,33,34).…”

A Japanese Case with Nasu-Hakola Disease of DAP12 Gene Mutation Exhibiting Precuneus Hypoperfusion

“…There has been a report of a case of a TREM2 gene mutation in a patient who manifested symptoms of dementia without exhibiting bone lesions (9). Similarly, there have been two reported cases of heterozygous carriers of the mutated allele of TREM2 gene mutation who had profound visuo-spatial memory impairment without exhibiting bone lesions and whose SPECT study revealed the diminished blood flow to the basal ganglia (19).…”

“…However, without such bone lesions, diagnosis can be very difficult. According to Chouery et al, some patients in whom the mutation of the TREM2 gene was present developed early-onset dementia without exhibiting bone lesions (9). In such patients, genetic testing may be needed to The testing was performed when the patient was 35 years old, before the onset of convulsive seizures.…”

Signal Regulatory Protein-β1

“…11,12,21 Interestingly, loss-of-function mutations of either TREM2 or DAP12 are responsible for a chronic neurodegenerative disease named Nasu-Hakola. 33 Patients with mutations of TREM2 show as a major symptom pure early-onset dementia, 34 whereas patients with DAP12 mutations have dementia and bone cysts. 35 Here, we aimed to identify new microglial receptors that have a phagocytic ITAM signaling capacity and are involved in clearance of A␤ in AD.…”