Details

Autor(en) / Beteiligte

• Pottier, Cyril
• Ravenscroft, Thomas A
• Brown, Patricia H
• Finch, NiCole A
• Baker, Matt
• Parsons, Meeia
• Asmann, Yan W
• Ren, Yingxue
• Christopher, Elizabeth
• Levitch, Denise
• van Blitterswijk, Marka
• Cruchaga, Carlos
• Campion, Dominique
• Nicolas, Gaël
• Richard, Anne-Claire
• Guerreiro, Rita
• Bras, Jose T
• Zuchner, Stephan
• Gonzalez, Michael A
• Bu, Guojun
• Younkin, Steven
• Knopman, David S
• Josephs, Keith A
• Parisi, Joseph E
• Petersen, Ronald C
• Ertekin-Taner, Nilüfer
• Graff-Radford, Neill R
• Boeve, Bradley F
• Dickson, Dennis W
• Rademakers, Rosa

Titel

TYROBP genetic variants in early-onset Alzheimer's disease

Ist Teil von

• Neurobiology of aging, 2016-12, Vol.48, p.222.e9-222.e15

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• Abstract We aimed to identify new candidate genes potentially involved in early-onset Alzheimer's disease (EOAD). Exome sequencing was conducted on 45 EOAD patients with either a family history of Alzheimer's disease (AD, <65 years) or an extremely early age at the onset (≤55 years) followed by multiple variant filtering according to different modes of inheritance. We identified 29 candidate genes potentially involved in EOAD, of which the gene TYROBP , previously implicated in AD, was selected for genetic and functional follow-up. Using 3 patient cohorts, we observed rare coding TYROBP variants in 9 out of 1110 EOAD patients, whereas no such variants were detected in 1826 controls ( p  = 0.0001), suggesting that at least some rare TYROBP variants might contribute to EOAD risk. Overexpression of the p.D50_L51ins14 TYROBP mutant led to a profound reduction of TREM2 expression, a well-established risk factor for AD. This is the first study supporting a role for genetic variation in TYROBP in EOAD, with in vitro support for a functional effect of the p.D50_L51ins14 TYROBP mutation on TREM2 expression.