A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease

Hartl, Daniela and May, Patrick and Gu, Wei and Mayhaus, Manuel and Pichler, Sabrina and Spaniol, Christian and Glaab, Enrico and Bobbili, Dheeraj Reddy and Antony, Paul and Koegelsberger, Sandra and Kurz, Alexander and Grimmer, Timo and Morgan, Kevin and Vardarajan, Badri N. and Reitz, Christiane and Hardy, John and Bras, Jose and Guerreiro, Rita and Balling, Rudi and Schneider, Jochen G. and Riemenschneider, Matthias (2018) A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease. Molecular Psychiatry . ISSN 1476-5578

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Abstract

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.

Item Type: Article
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
Identification Number: https://doi.org/10.1038/s41380-018-0091-8
Depositing User: Eprints, Support
Date Deposited: 11 Apr 2018 13:38
Last Modified: 11 Jul 2018 08:30
URI: http://eprints.nottingham.ac.uk/id/eprint/51095

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