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

Hartl, Daniela; May, Patrick; Gu, Wei; Mayhaus, Manuel; Pichler, Sabrina; Spaniol, Christian; Glaab, Enrico; Bobbili, Dheeraj Reddy; Antony, Paul; Koegelsberger, Sandra; Kurz, Alexander; Grimmer, Timo; Morgan, Kevin; Vardarajan, Badri N.; Reitz, Christiane; Hardy, John; Bras, Jose; Guerreiro, Rita; Balling, Rudi; Schneider, Jochen G.; Riemenschneider, Matthias

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.

Citation

Hartl, D., May, P., Gu, W., Mayhaus, M., Pichler, S., Spaniol, C., …Riemenschneider, M. (2020). A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease. Molecular Psychiatry, 25, 629–639. https://doi.org/10.1038/s41380-018-0091-8

• Journal Article Type: Article
• Acceptance Date: Apr 11, 2018
• Online Publication Date: Jul 9, 2018
• Publication Date: Mar 1, 2020
• Deposit Date: Apr 11, 2018
• Publicly Available Date: Jul 11, 2018
• Journal: Molecular Psychiatry
• Print ISSN: 1359-4184
• Electronic ISSN: 1476-5578
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 25
• Pages: 629–639
• DOI: https://doi.org/10.1038/s41380-018-0091-8
• Public URL: https://nottingham-repository.worktribe.com/output/945652
• Publisher URL: https://www.nature.com/articles/s41380-018-0091-8