Reference : A rare loss-of function variant of ADAM17 is associated with late-onset familial Alzh...

	Document type :	Scientific journals : Article
	Discipline(s) :	Life sciences : Biotechnology Life sciences : Multidisciplinary, general & others Human health sciences : Neurology
	Focus Areas :	Systems Biomedicine
	To cite this reference:	http://hdl.handle.net/10993/35708

Title :	A rare loss-of function variant of ADAM17 is associated with late-onset familial Alzheimer disease
Language :	English
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 []
	* These authors have contributed equally to this work.
Publication date :	9-Jul-2018
Journal title :	Molecular Psychiatry
Publisher :	Nature Publishing Group
Peer reviewed :	Yes (verified by ORBilu)
Audience :	International
ISSN :	1359-4184
e-ISSN :	1476-5578
City :	Houndmills
Country :	United Kingdom
Keywords :	[en] 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 centres :	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
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’
Target :	Researchers ; Professionals ; Students ; General public
Permalink :	http://hdl.handle.net/10993/35708
DOI :	10.1038/s41380-018-0091-8
Other URL :	https://www.nature.com/articles/s41380-018-0091-8

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