Reference : IDENTIFICATION OF A RARE GENE VARIANT THAT IS ASSOCIATED WITH FAMILIAL ALZHEIMER DISE...

	Document type :	Scientific congresses, symposiums and conference proceedings : Paper published in a journal
	Discipline(s) :	Life sciences : Genetics & genetic processes
	Focus Areas :	Systems Biomedicine
	To cite this reference:	http://hdl.handle.net/10993/32669

Title :	IDENTIFICATION OF A RARE GENE VARIANT THAT IS ASSOCIATED WITH FAMILIAL ALZHEIMER DISEASE AND REGULATES APP EXPRESSION
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 []
	Glaab, Enrico [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
	Antony, Paul [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
	Bobbili, Dheeraj Reddy [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
	Köglsberger, Sandra [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
	Pichler, Sabrina []
	Spaniol, Christian []
	Kurz, Alexander []
	Balling, Rudi [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
	Schneider, Jochen [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
	Riemenschneider, Matthias []
Publication date :	2017
Journal title :	Alzheimer's & Dementia : The Journal of the Alzheimer's Association
Publisher :	Elsevier
Volume :	13
Issue/season :	7, Supplement
Pages :	P648
Peer reviewed :	Yes
Audience :	International
ISSN :	1552-5260
e-ISSN :	1552-5279
City :	Orlando
Country :	FL
Event name :	Alzheimer’s Association International Conference (AAIC)
Event date :	July 16-20
Event organizer :	Volume 13, Issue 7, Supplement, July 2017, Pages P648
Event place (city) :	London
Keywords :	[en] Alzheimer's disease ; Neurodegeneration ; Genetics
Abstract :	[en] Background Genetic mutations leading to familial forms of Alzheimer disease (AD) have so far been reported for a few genes including APP, PSEN1 and PSEN2, UNC5C, PLD3, ABCA7, TTC3, and possibly ADAM10. With the advent of whole exome and whole genome sequencing approaches new genes and mutations are likely to be identified. Methods We analyzed the genetic cause of AD in a large multiplex family with an autosomal-dominant pattern of inheritance with LOAD. The family lacked pathogenic mutations of known AD genes. We performed whole-genome sequencing (WGS) in six family members (two affected and four unaffected) and prioritized rare, potential damaging, variants that segregated with disease. Variants were further characterized by subsequent molecular analyzes in human brain and cell culture models. Results We identified a single rare nonsynonymous variant co-segregating with AD. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to a loss-of-function of the gene. We further found a strong negative correlation between the identified gene and APP gene expression in human brain and in cells over-expressing the gene. The negative regulation of APP expression was only observed for the wt gene, but not for mutated forms, thus causing beside the loss of enzyme function a decoupling of both APPexpression and subsequent beta-amyloid formation. The identity of the gene will be presented on the conference. Conclusions This novel pathway strongly supports a causative association of the identified gene with 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
Target :	Researchers
Permalink :	http://hdl.handle.net/10993/32669
DOI :	10.1016/j.jalz.2017.06.758
Other URL :	http://www.sciencedirect.com.proxy.bnl.lu/science/article/pii/S1552526017309913

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