Reference : A rare loss-of function variant of ADAM17 is associated with late-onset familial Alzh... |
Scientific journals : Article | |||
Life sciences : Biotechnology Life sciences : Multidisciplinary, general & others Human health sciences : Neurology | |||
Systems Biomedicine | |||
http://hdl.handle.net/10993/35708 | |||
A rare loss-of function variant of ADAM17 is associated with late-onset familial Alzheimer disease | |
English | |
Hartl, Daniela* [] | |
May, Patrick* ![]() | |
Gu, Wei* ![]() | |
Mayhaus, Manuel [] | |
Pichler, Sabrina [] | |
Spaniol, Christian [] | |
Glaab, Enrico ![]() | |
Bobbili, Dheeraj Reddy ![]() | |
Antony, Paul ![]() | |
Köglsberger, Sandra ![]() | |
Kurz, Alexander [] | |
Grimmer, Timo [] | |
Morgan, Kevin [] | |
Vardarajan, Badri N. [] | |
Reitz, Christiane [] | |
Hardy, John [] | |
Bras, Jose [] | |
Guerreiro, Rita [] | |
AESG [] | |
Balling, Rudi ![]() | |
Schneider, Jochen ![]() | |
Riemenschneider, Matthias [] | |
* These authors have contributed equally to this work. | |
9-Jul-2020 | |
Molecular Psychiatry | |
Nature Publishing Group | |
25 | |
3 | |
629-639 | |
Yes (verified by ORBilu) | |
International | |
1359-4184 | |
1476-5578 | |
Houndmills | |
United Kingdom | |
[en] Alzheimer's disease ; genetic risk factors ; gene expression ; transcriptomics ; ADAM17 ; amyloid ; single nucleotide variation ; neuroscience ; genetics ; GWAS ; NGS ; sequencing | |
[en] 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, the UK and the 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 α-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. | |
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) ; Luxembourg Centre for Systems Biomedicine (LCSB): Biomedical Data Science (Glaab Group) ; Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) ; Luxembourg Centre for Systems Biomedicine (LCSB): Medical Translational Research (J. Schneider Group) ; University of Luxembourg: High Performance Computing - ULHPC | |
University of Luxembourg (UL) -Institute for Systems Biology (ISB) Strategic Partnership by ‘Le plan Technologies de la Sante par le Gouvernment du Grand-Duche de Luxembourg’ | |
Researchers ; Professionals ; Students ; General public | |
http://hdl.handle.net/10993/35708 | |
10.1038/s41380-018-0091-8 | |
https://www.nature.com/articles/s41380-018-0091-8 |
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