Abstract
Recent evidence suggests that rare genetic variants within the TREM2 gene are associated with increased risk of Alzheimer's disease. TREM2 mutations are the genetic basis for a condition characterized by polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) and an early-onset dementia syndrome. TREM2 is important in the phagocytosis of apoptotic neuronal cells by microglia in the brain. Loss of function might lead to an impaired clearance and to accumulation of necrotic debris and subsequent neurodegeneration. In this study, we investigated a consanguineous family segregating autosomal recessive behavioral variant FTLD from Antioquia, Colombia. Exome sequencing identified a nonsense mutation in TREM2 (p.Trp198X) segregating with disease. Next, using a cohort of clinically characterized and neuropathologically verified sporadic AD cases and controls, we report replication of the AD risk association at rs75932628 within TREM2 and demonstrate that TREM2 is significantly overexpressed in the brain tissue from AD cases. These data suggest that a mutational burden in TREM2 may serve as a risk factor for neurodegenerative disease in general, and that potentially this class of TREM2 variant carriers with dementia should be considered as having a molecularly distinct form of neurodegenerative disease.
| Original language | English (US) |
|---|---|
| Journal | Neurobiology of Aging |
| Volume | 34 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2013 |
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Keywords
- Alzheimer's disease
- FTLD
- Neurodegeneration
- TREM2
ASJC Scopus subject areas
- Clinical Neurology
- Neuroscience(all)
- Aging
- Developmental Biology
- Geriatrics and Gerontology
Cite this
Variants in triggering receptor expressed on myeloid cells 2 are associated with both behavioral variant frontotemporal lobar degeneration and Alzheimer's disease. / Giraldo, Margarita; Lopera, Francisco; Siniard, Ashley L.; Corneveaux, Jason J.; Schrauwen, Isabelle; Carvajal, Julian; Muñoz, Claudia; Ramirez-Restrepo, Manuel; Gaiteri, Chris; Myers, Amanda J.; Caselli, Richard John; Kosik, Kenneth S.; Reiman, Eric M.; Huentelman, Matthew J.
In: Neurobiology of Aging, Vol. 34, No. 8, 08.2013.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Variants in triggering receptor expressed on myeloid cells 2 are associated with both behavioral variant frontotemporal lobar degeneration and Alzheimer's disease
AU - Giraldo, Margarita
AU - Lopera, Francisco
AU - Siniard, Ashley L.
AU - Corneveaux, Jason J.
AU - Schrauwen, Isabelle
AU - Carvajal, Julian
AU - Muñoz, Claudia
AU - Ramirez-Restrepo, Manuel
AU - Gaiteri, Chris
AU - Myers, Amanda J.
AU - Caselli, Richard John
AU - Kosik, Kenneth S.
AU - Reiman, Eric M.
AU - Huentelman, Matthew J.
PY - 2013/8
Y1 - 2013/8
N2 - Recent evidence suggests that rare genetic variants within the TREM2 gene are associated with increased risk of Alzheimer's disease. TREM2 mutations are the genetic basis for a condition characterized by polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) and an early-onset dementia syndrome. TREM2 is important in the phagocytosis of apoptotic neuronal cells by microglia in the brain. Loss of function might lead to an impaired clearance and to accumulation of necrotic debris and subsequent neurodegeneration. In this study, we investigated a consanguineous family segregating autosomal recessive behavioral variant FTLD from Antioquia, Colombia. Exome sequencing identified a nonsense mutation in TREM2 (p.Trp198X) segregating with disease. Next, using a cohort of clinically characterized and neuropathologically verified sporadic AD cases and controls, we report replication of the AD risk association at rs75932628 within TREM2 and demonstrate that TREM2 is significantly overexpressed in the brain tissue from AD cases. These data suggest that a mutational burden in TREM2 may serve as a risk factor for neurodegenerative disease in general, and that potentially this class of TREM2 variant carriers with dementia should be considered as having a molecularly distinct form of neurodegenerative disease.
AB - Recent evidence suggests that rare genetic variants within the TREM2 gene are associated with increased risk of Alzheimer's disease. TREM2 mutations are the genetic basis for a condition characterized by polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) and an early-onset dementia syndrome. TREM2 is important in the phagocytosis of apoptotic neuronal cells by microglia in the brain. Loss of function might lead to an impaired clearance and to accumulation of necrotic debris and subsequent neurodegeneration. In this study, we investigated a consanguineous family segregating autosomal recessive behavioral variant FTLD from Antioquia, Colombia. Exome sequencing identified a nonsense mutation in TREM2 (p.Trp198X) segregating with disease. Next, using a cohort of clinically characterized and neuropathologically verified sporadic AD cases and controls, we report replication of the AD risk association at rs75932628 within TREM2 and demonstrate that TREM2 is significantly overexpressed in the brain tissue from AD cases. These data suggest that a mutational burden in TREM2 may serve as a risk factor for neurodegenerative disease in general, and that potentially this class of TREM2 variant carriers with dementia should be considered as having a molecularly distinct form of neurodegenerative disease.
KW - Alzheimer's disease
KW - FTLD
KW - Neurodegeneration
KW - TREM2
UR - http://www.scopus.com/inward/record.url?scp=84877618309&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84877618309&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2013.02.016
DO - 10.1016/j.neurobiolaging.2013.02.016
M3 - Article
C2 - 23582655
AN - SCOPUS:84877618309
VL - 34
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
IS - 8
ER -