Using Exome Sequencing to Reveal Mutations in TREM2 Presenting as a Frontotemporal Dementia–like Syndrome Without Bone Involvement

Abstract

To identify new genes and risk factors associated with frontotemporal dementia (FTD). Several genes and loci have been associated with different forms of FTD, but a large number of families with dementia do not harbor mutations in these genes.Design: Whole-exome sequencing and whole-genome genotyping were performed in all patients. Genetic variants obtained from whole-exome sequencing were integrated with the data obtained from whole-genome genotyping.

Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)

“…Recently, the missense TREM2-R47H mutation has been identified and validated as a risk variant for LOAD (6,7,11,(15)(16)(17)(18)(19). Although numerous studies have investigated the genetic link between TREM2 variants and neurodegenerative diseases, only two other studies have empirically tested the functional outcome of disease-associated mutations (23,51).…”

CNS inflammation and neurodegeneration

“…DAP12 forms a receptor-signaling complex with TREM2 and triggers activation of immune responses to macrophages and microglia. A rare missense mutation in the gene encoding TREM2 confers risk of late-onset AD (80,81) and frontotemporal dementia (82), possibly due to impaired clearance of proteins by macrophages and microglia.…”

Microglia in prion diseases

“…TREM2 facilitates phagocytosis of apoptotic neurons and bacteria, thereby suppressing inflammation (95,96). Dysfunctional variants of TREM2 have been identified as major genetic risk factors for AD and other neurodegenerative conditions (97)(98)(99)(100)(101). Ablation of Trem2 in a mouse model of AD (5xFAD) resulted in increased hippocampal Aβ burden and accelerated loss of cortical neurons.…”