Reference : IDENTIFICATION OF A RARE GENE VARIANT THAT IS ASSOCIATED WITH FAMILIAL ALZHEIMER DISE...
Scientific congresses, symposiums and conference proceedings : Paper published in a journal
Life sciences : Genetics & genetic processes
Systems Biomedicine
http://hdl.handle.net/10993/32669
IDENTIFICATION OF A RARE GENE VARIANT THAT IS ASSOCIATED WITH FAMILIAL ALZHEIMER DISEASE AND REGULATES APP EXPRESSION
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 []
Glaab, Enrico mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Antony, Paul mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Bobbili, Dheeraj Reddy mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Köglsberger, Sandra mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Pichler, Sabrina []
Spaniol, Christian []
Kurz, Alexander []
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 []
2017
Alzheimer's & Dementia : The Journal of the Alzheimer's Association
Elsevier
13
7, Supplement
P648
Yes
International
1552-5260
1552-5279
Orlando
FL
Alzheimer’s Association International Conference (AAIC)
July 16-20
Volume 13, Issue 7, Supplement, July 2017, Pages P648
London
[en] Alzheimer's disease ; Neurodegeneration ; Genetics
[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.
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
Researchers
http://hdl.handle.net/10993/32669
10.1016/j.jalz.2017.06.758
http://www.sciencedirect.com.proxy.bnl.lu/science/article/pii/S1552526017309913

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