Article (Scientific journals)
A rare loss-of function variant of ADAM17 is associated with late-onset familial Alzheimer disease
Hartl, Daniela; MAY, Patrick; GU, Wei et al.
2020In Molecular Psychiatry, 25 (3), p. 629-639
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Keywords :
Alzheimer's disease; genetic risk factors; gene expression; transcriptomics; ADAM17; amyloid; single nucleotide variation; neuroscience; genetics; GWAS; NGS; sequencing
Abstract :
[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.
Research center :
- 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)
ULHPC - University of Luxembourg: High Performance Computing
Disciplines :
Life sciences: Multidisciplinary, general & others
Biotechnology
Neurology
Author, co-author :
Hartl, Daniela 
MAY, Patrick   ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
GU, Wei  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Mayhaus, Manuel
Pichler, Sabrina
Spaniol, Christian
GLAAB, Enrico  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
BOBBILI, Dheeraj Reddy ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
ANTONY, Paul ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Köglsberger, Sandra ;  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 ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
SCHNEIDER, Jochen ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Riemenschneider, Matthias
More authors (12 more) Less
 These authors have contributed equally to this work.
External co-authors :
yes
Language :
English
Title :
A rare loss-of function variant of ADAM17 is associated with late-onset familial Alzheimer disease
Publication date :
09 July 2020
Journal title :
Molecular Psychiatry
ISSN :
1359-4184
eISSN :
1476-5578
Publisher :
Nature Publishing Group, Houndmills, United Kingdom
Volume :
25
Issue :
3
Pages :
629-639
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
Funders :
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’
Available on ORBilu :
since 17 May 2018

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