TY  - INPR
UR  - http://doi.org/10.1038/s41380-018-0091-8
SN  - 1476-5578
N2  - Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, UK, and USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 alpha-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Aß formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD.
ID  - discovery10053021
A1  - Hartl, D
A1  - May, P
A1  - Gu, W
A1  - Mayhaus, M
A1  - Pichler, S
A1  - Spaniol, C
A1  - Glaab, E
A1  - Bobbili, DR
A1  - Antony, P
A1  - Koegelsberger, S
A1  - Kurz, A
A1  - Grimmer, T
A1  - Morgan, K
A1  - Vardarajan, BN
A1  - Reitz, C
A1  - Hardy, J
A1  - Bras, J
A1  - Guerreiro, R
A1  - Balling, R
A1  - Schneider, JG
A1  - Riemenschneider, M
A1  - AESG
JF  - Molecular Psychiatry
Y1  - 2018/07/09/
AV  - public
TI  - A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease
N1  - Copyright © The Author(s) 2018. Open Access This article is licensed under a Creative Commons
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ER  -