A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease.

Autor: Hartl D; Department of Psychiatry and Psychotherapy, Saarland University Hospital, Saarland University, Homburg, Germany. daniela.hartl@uks.eu., May P; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg.; Institute for Systems Biology, Seattle, WA, USA., Gu W; Department of Psychiatry and Psychotherapy, Saarland University Hospital, Saarland University, Homburg, Germany.; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg., Mayhaus M; Department of Psychiatry and Psychotherapy, Saarland University Hospital, Saarland University, Homburg, Germany., Pichler S; Department of Psychiatry and Psychotherapy, Saarland University Hospital, Saarland University, Homburg, Germany., Spaniol C; Department of Psychiatry and Psychotherapy, Saarland University Hospital, Saarland University, Homburg, Germany., Glaab E; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg., Bobbili DR; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg., Antony P; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg., Koegelsberger S; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg., Kurz A; Department of Psychiatry and Psychotherapy, Klinikum Rechts der Isar, TU-Muenchen, Munich, Germany., Grimmer T; Department of Psychiatry and Psychotherapy, Klinikum Rechts der Isar, TU-Muenchen, Munich, Germany., Morgan K; School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK., Vardarajan BN; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York City, NY, USA.; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York City, NY, USA.; Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York City, NY, USA., Reitz C; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York City, NY, USA.; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York City, NY, USA.; Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York City, NY, USA.; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York City, NY, USA., Hardy J; Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK., Bras J; Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.; UK Dementia Research Institute at UCL (UK DRI), London, UK.; Department of Medical Sciences, Institute of Biomedicine-iBiMED, University of Aveiro, Aveiro, Portugal., Guerreiro R; Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.; UK Dementia Research Institute at UCL (UK DRI), London, UK.; Department of Medical Sciences, Institute of Biomedicine-iBiMED, University of Aveiro, Aveiro, Portugal., Balling R; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg., Schneider JG; Department of Psychiatry and Psychotherapy, Saarland University Hospital, Saarland University, Homburg, Germany.; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg., Riemenschneider M; Department of Psychiatry and Psychotherapy, Saarland University Hospital, Saarland University, Homburg, Germany.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2020 Mar; Vol. 25 (3), pp. 629-639. Date of Electronic Publication: 2018 Jul 09.
DOI: 10.1038/s41380-018-0091-8
Abstrakt: 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, UK, and 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 alpha-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.
Databáze: MEDLINE
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