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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

Authors

Daniela Hartl

Patrick May

Wei Gu

Manuel Mayhaus

Sabrina Pichler

Christian Spaniol

Enrico Glaab

Dheeraj Reddy Bobbili

Paul Antony

Sandra Koegelsberger

Alexander Kurz

Timo Grimmer

KEVIN MORGAN kevin.morgan@nottingham.ac.uk
Professor of Human Genomics and Molecular Genetics

Badri N. Vardarajan

Christiane Reitz

John Hardy

Jose Bras

Rita Guerreiro

Rudi Balling

Jochen G. Schneider

Matthias Riemenschneider



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 http://eprints.nottingham.ac.uk/id/eprint/51095
Publisher URL https://www.nature.com/articles/s41380-018-0091-8
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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