A rare heterozygous TREM2 coding variant identified in familial clustering of dementia affects an intrinsically disordered protein region and function of TREM2.
[en] Rare coding variants in the triggering receptor expressed on myeloid cells-2 (TREM2) gene have been associated with Alzheimer disease (AD) and homozygous TREM2 loss-of-function variants have been reported in families with monogenic frontotemporal-like dementia with/without bone abnormalities. In a whole-exome sequencing study of a family with probable AD-type dementia without pathogenic variants in known autosomal dominant dementia disease genes and negative for the apolipoprotein E (APOE) ε4 allele, we identified an extremely rare TREM2 coding variant, that is, a glycine-to-tryptophan substitution at amino acid position 145 (NM_018965.3:c.433G>T/p.[Gly145Trp]). This alteration is found in only 1 of 251,150 control alleles in gnomAD. It was present in both severely affected as well as in another putatively affected and one 61 years old as yet unaffected family member suggesting incomplete penetrance and/or a variable age of onset. Gly145 maps to an intrinsically disordered region (IDR) of TREM2 between the immunoglobulin-like and transmembrane domain. Subsequent cellular studies showed that the variant led to IDR shortening and structural changes of the mutant protein resulting in an impairment of cellular responses upon receptor activation. Our results, suggest that a p.(Gly145Trp)-induced structural disturbance and functional impairment of TREM2 may contribute to the pathogenesis of an AD-like form of dementia.
Disciplines :
Neurology
Author, co-author :
Karsak, Meliha ✱; Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany
Glebov, Konstantin ✱; Department of Neurology, University of Bonn, Bonn, Germany
Scheffold, Marina; Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany ; Institute of Pharmacology and Toxicology, University of Ulm, Ulm, Germany
Bajaj, Thomas; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany
Kawalia, Amit; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany
Karaca, Ilker; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany
Rading, Sebastian; Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany
Kornhuber, Johannes; Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
Peters, Oliver; Department of Psychiatry, Charité University Medicine, Berlin, Germany
Diez-Fairen, Monica; Department of Neurology, Memory and Movement Disorders Units, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain ; Fundació Docència i Recerca Mútua Terrassa, University Hospital Mútua de Terrassa, Terrassa, Barcelona, Spain
Frölich, Lutz; Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
Hüll, Michael; Center for Psychiatry, Clinic for Geriatric Psychiatry and Psychotherapy Emmendingen and Department of Psychiatry and Psychotherapy, University of Freiburg, Freiburg, Germany
Wiltfang, Jens; Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany ; German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
Scherer, Martin; Department of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Riedel-Heller, Steffi; Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany
Schneider, Anja; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
HENEKA, Michael ; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
Fliessbach, Klaus; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany
Sharaf, Ahmed; Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany
Thiele, Holger; Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
Lennarz, Martina; Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany
Jessen, Frank; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany
Maier, Wolfgang; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Kubisch, Christian; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Ignatova, Zoya; Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany
Nürnberg, Peter; Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany ; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
Pastor, Pau; Department of Neurology, Memory and Movement Disorders Units, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain ; Fundació Docència i Recerca Mútua Terrassa, University Hospital Mútua de Terrassa, Terrassa, Barcelona, Spain
Walter, Jochen ; Department of Neurology, University of Bonn, Bonn, Germany
Ramirez, Alfredo ; Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty, University of Cologne, Cologne, Germany ; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn, Bonn, Germany
✱ These authors have contributed equally to this work.
External co-authors :
yes
Language :
English
Title :
A rare heterozygous TREM2 coding variant identified in familial clustering of dementia affects an intrinsically disordered protein region and function of TREM2.
Deutsche Forschungsgemeinschaft Bundesministerium für Bildung und Forschung Alzheimer Forschung Initiative
Funding text :
We thank all patients and controls for their participation in this project. This study was funded in part by the German Federal Ministry of Education and Research (grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, and 01GI0434; grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716, and 01ET1006B). Part of this study was also funded by grants to Jochen Walter: DFG WA1477/6-2 (KFO177), Innovative Medicines Initiative 2 Joint Undertaking (IMI2 JU), grant/award number: No 115976 (PHAGO), and to KG (Alzheimer Forschung Initiative e.V. grant 16019). Center for Applied Medical Research, University of Navarra (CIMA; Pamplona, Spain) contributed to this study.
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