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* mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Gu, Wei* mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Mayhaus, Manuel []
Pichler, Sabrina []
Spaniol, Christian []
Glaab, Enrico mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Bobbili, Dheeraj Reddy mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Antony, Paul mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Köglsberger, Sandra mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Kurz, Alexander []
Grimmer, Timo []
Morgan, Kevin []
Vardarajan, Badri N. []
Reitz, Christiane []
Hardy, John []
Bras, Jose []
Guerreiro, Rita []
AESG []
Balling, Rudi mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Schneider, Jochen mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Riemenschneider, Matthias []
* These authors have contributed equally to this work.
In press
Molecular Psychiatry
Nature Publishing Group
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
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