Adaptor Proteins, Signal Transducing; DNA-Binding Proteins; SQSTM1 protein, human; Sequestosome-1 Protein; Adaptor Proteins, Signal Transducing/genetics; Adult; Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Animals; Cohort Studies; DNA Mutational Analysis; DNA-Binding Proteins/genetics; Europe; Female; Frontotemporal Lobar Degeneration/genetics; Frontotemporal Lobar Degeneration/pathology; Genetic Predisposition to Disease/genetics; Humans; International Cooperation; Male; Meta-Analysis as Topic; Middle Aged; Polymorphism, Single Nucleotide/genetics; ALS; FTLD; p62; Rare variants; Sequestosome 1; SQSTM1; Frontotemporal Lobar Degeneration; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Pathology and Forensic Medicine; Neurology (clinical); Cellular and Molecular Neuroscience
Abstract :
[en] Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.
Disciplines :
Neurology
Author, co-author :
van der Zee, Julie; Department of Molecular Genetics, VIB, Antwerp, Belgium
Van Langenhove, Tim; Department of Molecular Genetics, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium ; Department of Neurology, Antwerp University Hospital, Edegem, Belgium
Kovacs, Gabor G; Institute of Neurology, Neurodegenerative Diseases Group, Medical University of Vienna, Vienna, Austria
Dillen, Lubina; Department of Molecular Genetics, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Deschamps, William; Department of Molecular Genetics, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Engelborghs, Sebastiaan; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium ; Department of Neurology and Memory Clinic, Hospital Network Antwerp Middelheim and Hoge Beuken, Antwerp, Belgium
Matěj, Radoslav; Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague, Czech Republic ; Department of Neurology, Center of Clinical Neurosciences, Charles University in Prague, Prague, Czech Republic
Vandenbulcke, Mathieu; Brain and Emotion Laboratory, Department of Psychiatry, University of Leuven, Louvain, Belgium ; University Hospitals Leuven, Department of Neurosciences, University of Leuven, Louvain, Belgium
Sieben, Anne; Department of Molecular Genetics, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium ; Department of Neurology, University Hospital Ghent, Ghent, Belgium
Dermaut, Bart; Department of Neurology, University Hospital Ghent, Ghent, Belgium ; Center for Medical Genetics, University Hospital Ghent, Ghent, Belgium ; Inserm U744, Institut Pasteur de Lille, Université de Lille Nord de France, Lille, France
Smets, Katrien; Department of Molecular Genetics, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium ; Department of Neurology, Antwerp University Hospital, Edegem, Belgium
Van Damme, Philip; Department of Neurology, University Hospitals Leuven, University of Leuven, Louvain, Belgium ; Laboratory for Neurobiology, Vesalius Research Center, VIB, Louvain, Belgium
Merlin, Céline; Department of Molecular Genetics, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Laureys, Annelies; Department of Molecular Genetics, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Van Den Broeck, Marleen; Department of Molecular Genetics, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Mattheijssens, Maria; Department of Molecular Genetics, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Peeters, Karin; Department of Molecular Genetics, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Benussi, Luisa; NeuroBioGen Lab.-Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
Binetti, Giuliano; NeuroBioGen Lab.-Memory Clinic, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
Ghidoni, Roberta; Proteomics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
Borroni, Barbara; Neurology Unit, University of Brescia, Brescia, Italy
Padovani, Alessandro; Neurology Unit, University of Brescia, Brescia, Italy
Archetti, Silvana; III Laboratory of Analysis, Brescia Hospital, Brescia, Italy
Pastor, Pau; Division of Neurosciences, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain ; Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain ; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain
Razquin, Cristina; Division of Neurosciences, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain
Ortega-Cubero, Sara; Division of Neurosciences, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain ; Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain ; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain
Hernández, Isabel; Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
Boada, Mercè; Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
Ruiz, Agustín; Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain
de Mendonça, Alexandre; Faculty of Medicine, Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal
Miltenberger-Miltényi, Gabriel; Faculty of Medicine, Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal
do Couto, Frederico Simões; Faculty of Medicine, Institute of Molecular Medicine, University of Lisbon, Lisbon, Portugal ; Hospital Santa Maria, Lisbon, Portugal
Sorbi, Sandro; Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
Nacmias, Benedetta; Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
Bagnoli, Silvia; Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
Graff, Caroline; Karolinska Institutet, Department of Neurobiology, Care Sciences and Society (NVS), KI-Alzheimer Disease Research Center, Stockholm, Sweden ; Genetics Unit, Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden
Chiang, Huei-Hsin; Karolinska Institutet, Department of Neurobiology, Care Sciences and Society (NVS), KI-Alzheimer Disease Research Center, Stockholm, Sweden ; Genetics Unit, Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden
Thonberg, Håkan; Genetics Unit, Department of Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden
Perneczky, Robert; School of Public Health, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London W6 8RP, United Kingdom ; West London Cognitive Disorders Treatment and Research Unit, West London Mental Health Trust, London TW8 8DS, United Kingdom ; Department of Psychiatry and Psychotherapy, Technische Universität München, 81675 Munich, Germany
Diehl-Schmid, Janine; Department of Psychiatry and Psychotherapy, Technische Universität München, 81675 Munich, Germany
Alexopoulos, Panagiotis; Department of Psychiatry and Psychotherapy, Technische Universität München, 81675 Munich, Germany
Frisoni, Giovanni B; Hôpitaux Universitaires de Genève, Université de Genève, Geneva, Switzerland ; IRCCS Fatebenefratelli, Brescia, Italy
Synofzik, Matthis; Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, Centre of Neurology, Tübingen, Germany ; German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Maetzler, Walter; Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, Centre of Neurology, Tübingen, Germany ; German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
vom Hagen, Jennifer Müller; Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, Centre of Neurology, Tübingen, Germany ; German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Schöls, Ludger; Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, Centre of Neurology, Tübingen, Germany ; German Research Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
Haack, Tobias B; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany ; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
Strom, Tim M; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany ; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
Prokisch, Holger; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany ; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany
Dols-Icardo, Oriol; Department of Neurology, Hospital de la Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain ; Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Clarimón, Jordi; Department of Neurology, Hospital de la Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain ; Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Lleó, Alberto; Department of Neurology, Hospital de la Santa Creu I Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain ; Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain
Santana, Isabel; Neurology Department, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal ; Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Almeida, Maria Rosário; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
Santiago, Beatriz; Neurology Department, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal
HENEKA, Michael ; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), University of Bonn, Bonn, Germany
Jessen, Frank; German Center for Neurodegenerative Diseases (DZNE), University of Bonn, Bonn, Germany ; Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany
Ramirez, Alfredo; Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany ; Institute of Human Genetics, University of Bonn, Bonn, Germany
Sanchez-Valle, Raquel; Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Barcelona, Spain
Llado, Albert; Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Barcelona, Spain
Gelpi, Ellen; Neurological Tissue Bank of the Biobanc-Hospital Clinic, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
Sarafov, Stayko; Department of Neurology, Medical University Sofia, Sofia, Bulgaria
Tournev, Ivailo; Department of Neurology, Medical University Sofia, Sofia, Bulgaria ; Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria
Jordanova, Albena; Department of Molecular Genetics, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium ; Department of Biochemistry, Molecular Medicine Center, Medical University, Sofia, Sofia, Bulgaria
Parobkova, Eva; Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague, Czech Republic
Fabrizi, Gian Maria; Department of Neurological and Movement Sciences, University of Verona, Verona, Italy
Testi, Silvia; Department of Neurological and Movement Sciences, University of Verona, Verona, Italy
Salmon, Eric; Cyclotron Research Centre, University of Liege and Memory Clinic, CHU Liege, Liege, Belgium
Ströbel, Thomas; Institute of Neurology, Neurodegenerative Diseases Group, Medical University of Vienna, Vienna, Austria
Santens, Patrick; Department of Neurology, University Hospital Ghent, Ghent, Belgium
Robberecht, Wim; Department of Neurology, University Hospitals Leuven, University of Leuven, Louvain, Belgium ; Laboratory for Neurobiology, Vesalius Research Center, VIB, Louvain, Belgium
De Jonghe, Peter; Department of Molecular Genetics, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium ; Department of Neurology, Antwerp University Hospital, Edegem, Belgium
Martin, Jean-Jacques; Department of Molecular Genetics, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Cras, Patrick; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium ; Department of Neurology, Antwerp University Hospital, Edegem, Belgium
Vandenberghe, Rik; University Hospitals Leuven, Department of Neurosciences, University of Leuven, Louvain, Belgium ; Department of Neurology, University of Leuven, University Hospitals Leuven Gasthuisberg, Louvain, Belgium
De Deyn, Peter Paul; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium ; Department of Neurology and Memory Clinic, Hospital Network Antwerp Middelheim and Hoge Beuken, Antwerp, Belgium ; Department of Neurology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
Cruts, Marc; Department of Molecular Genetics, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Sleegers, Kristel; Department of Molecular Genetics, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Van Broeckhoven, Christine; Department of Molecular Genetics, VIB, Antwerp, Belgium ; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
genetic Service Facility for their support of the genetic analyses and to the different neurological centers for their contribution to the diagnosis and sampling of patients. The data generation for this paper was in part funded by the Metlife Award for Medical research to C.V.B., USA; the Belgian Science Policy Office (BelSPO) Interuniversity Attraction Poles program, the Flemish government support to the european Initiative on Centers of excellence in Neurodegeneration (CoeN), the Flemish government initiated Methusalem excellence program, the Alzheimer research Foundation (SAO/FrA), the Medical Foundation Queen elisabeth, the research Foundation Flanders (FWO), the Agency for Innovation by Science and Technology Flanders (IWT) and the University of Antwerp research Fund, Belgium. The FWO provided a postdoctoral fellowship to J.v.d.Z. and a clinical investigatorship to P.V.D. The Brescia IRCCS Fatebenefratelli site was funded by the ricerca Corrente, Italian Ministry of Health. r.g. was funded by Fondazione CArIPlO, grant Number 2009-2633. The Barcelona ACE site thank the patients and controls who participated in this project. We are indebted to Trinitat Port-Carbó and her family who are supporting Fundació ACe research programs. The Lisbon site acknowledges a grant by grunenthal. The Florence site acknowledges Prin 2010-prot. 2010PWNJXK; Cassa di rispario di Firenze e Cassa di risparmio di Pistoia e Pescia. The Stockholm site was financially supported by the Programme in Neuroscience at Karolin-ska Institutet (StratNeuro); the regional agreement on medical training and clinical research (AlF) between Stockholm County Council and Karolinska Institutet; Swedish Alzheimer Foundation; Swedish research Council; Karolinska Institutet PhD-student funding; King gustaf V and Queen Victoria’s Free Mason Foundation; the gun and Bertil Stohne’s Foundation, Foundation for Old Servants; Clinicians including Dr Vesna Jelic and Anne Börjesson-Hanson. For the Munich Institute of Human Genetics site H.P. was supported by the e-rare project geNOMIT (01gM1207), and the german Network for mitochondrial disorders (mitoNeT 01gM1113C). T.B.H. was supported by the NBIA disorders association. The Barcelona Sant Pau site was in part funded by a grant from the Spanish Ministry of economy and Competitiveness (grant Number PI12/01311) and CIBerNeD. The Pamplona Center for Applied Medical Research is indebted the UTe project from the Foundation for Applied Medical research (FIMA) and CIBerNeD. The Barcelona Neurological Tissue Bank site is indebted to the Neurological Tissue Bank of the IDIBAPS Biobanc for sample and data procurement. The Neurological Tissue Bank acknowledges all brain donors and relatives for generous brain donation for research and referring physicians. The Czech site was partially supported by grant IgA NT 12094-5 of grant Agency of the Czech Ministry of Health. The Verona site was in part supported by Fondazione Cariverona (grant Number 2009.1026 “Cognitive and behavioural disability in dementia and psychosis” to gMF). The Liege site was funded by the FNrS.
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