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

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Hartl, D., May, P., Gu, W., Mayhaus, M., Pichler, S., Spaniol, C., Glaab, E., Bobbili, D.R., Antony, P., Koegelsberger, S., Kurz, A., Grimmer, T., Morgan, K., Vardarajan, B.N., Reitz, C., Hardy, J., Bras, J., Guerreiro, R., Balling, R., Schneider, J.G., Riemenschneider, M., Sassi, C., Gibbs, J.R., Hernandez, D., Brookes, K.J. ORCID: 0000-0003-2427-2513, Guetta-Baranes, T., Francis, P.T., Lupton, M.K., Brown, K., Powell, J. and Singleton, A., 2018. A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease. Molecular Psychiatry. ISSN 1359-4184

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Official URL: http://doi.org/10.1038/s41380-018-0091-8

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:

Journal article

Publication Title:

Molecular Psychiatry

Creators:

Hartl, D., May, P., Gu, W., Mayhaus, M., Pichler, S., Spaniol, C., Glaab, E., Bobbili, D.R., Antony, P., Koegelsberger, S., Kurz, A., Grimmer, T., Morgan, K., Vardarajan, B.N., Reitz, C., Hardy, J., Bras, J., Guerreiro, R., Balling, R., Schneider, J.G., Riemenschneider, M., Sassi, C., Gibbs, J.R., Hernandez, D., Brookes, K.J., Guetta-Baranes, T., Francis, P.T., Lupton, M.K., Brown, K., Powell, J. and Singleton, A.

Publisher:

Nature Publishing Group

Date:

9 July 2018

ISSN:

1359-4184

Identifiers:

Number	Type
10.1038/s41380-018-0091-8	DOI

Rights:

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Divisions:

Schools > School of Science and Technology

Record created by:

Jonathan Gallacher

Date Added:

15 May 2019 09:27

Last Modified:

15 May 2019 09:27

URI:

https://irep.ntu.ac.uk/id/eprint/36547