Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration
Van der Zee, Julie (University of Antwerp (Anvers, Bèlgica))
Van Langenhove, Tim (University Hospital Antwerp (Anvers,Bèlgica))
Kovacs, Gabor G. (Medical University of Vienna (Viena, Àustria))
Dillen, Lubina (University of Antwerp (Anvers,Bèlgica))
Deschamps, William (University of Antwerp (Anvers,Bèlgica))
Engelborghs, Sebastiaan (Hospital Network Antwerp Middelheim and Hoge Beuken (Anvers,Bèlgica))
Matej, Radoslav (Charles University in Prague (Praga, República Txeca))
Vandenbulcke, Mathieu (University of Leuven (Lovaina, Bèlgica))
Sieben, Anne (Universitair Ziekenhuis Gent (Gant, Bèlgica))
Dermaut, Bart (Université de Lille Nord de France (França))
Smets, Katrien (University Hospital Antwerp (Anvers,Bèlgica))
Van Damme, Philip (University of Leuven (Lovaina, Bèlgica))
Merlin, Celine (University of Antwerp (Anvers,Bèlgica))
Laureys, Annelies (University of Antwerp (Anvers,Bèlgica))
Van Den Broeck, Marleen (University of Antwerp (Anvers,Bèlgica))
Mattheijssens, Maria (University of Antwerp (Anvers,Bèlgica))
Peeters, Karin (University of Antwerp (Anvers,Bèlgica))
Benussi, Luisa (IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli (Brescia, Itàlia))
Binetti, Giuliano (IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli (Brescia, Itàlia))
Ghidoni, Roberta (IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli (Brescia, Itàlia))
Borroni, Barbara (University of Brescia (Brescia, Itàlia))
Padovani, Alessandro (University of Brescia (Brescia, Itàlia))
Archetti, Silvana (Brescia Hospital (Brescia, Itàlia))
Pastor, Pau (Instituto de Salud Carlos III)
Razquín, Cristina (Universidad de Navarra (Pamplona, Navarra))
Ortega-Cubero, Sara (Instituto de Salud Carlos III)
Hernández, Isabel (Institut Català de Neurociències Aplicades)
Boada, Mercè (Institut Català de Neurociències Aplicades)
Ruiz Laza, Agustín (Institut Català de Neurociències Aplicades)
de Mendonça, Alexandre (University of Lisbon (Lisboa, Portugal))
Miltenberger-Miltényi, Gabriel (University of Lisbon (Lisboa, Portugal))
Simões do Couto, Frederico (Hospital Santa Maria (Lisboa, Portugal))
Sorbi, Sandro (Università degli Studi di Firenze)
Nacmias, Benedetta (Università degli Studi di Firenze)
Bagnoli, Silvia (Università degli Studi di Firenze)
Graff, Caroline (Karolinska University Hospital and Karolinska Institutet (Suècia))
Chiang, Huei-Hsin (Karolinska University Hospital and Karolinska Institutet (Suècia))
Thonberg, Hakan (Karolinska University Hospital and Karolinska Institutet (Suècia))
Perneczky, Robert (Technische Universität München (Múnic, Alemanya))
Diehl-Schmid, Janine (Technische Universität München (Múnic, Alemanya))
Alexopoulos, Panagiotis (Technische Universität München (Múnic, Alemanya))
Frisoni, Giovanni B. (IRCCS Fatebenefratelli (Brescia, Itàlia))
Bonvicini, Cristian (IRCCS Fatebenefratelli (Brescia, Itàlia))
Synofzik, Matthis (German Center for Neurodegenerative Diseases (DZNE))
Maetzler, Walter (German Center for Neurodegenerative Diseases (DZNE))
Vom Hagen, Jennifer Müller (German Center for Neurodegenerative Diseases (DZNE))
Schöls, Ludger (German Center for Neurodegenerative Diseases (DZNE))
Haack, Tobias B. (Helmholtz Zentrum München (Múnic, Alemanya))
Strom, Tim M. (Helmholtz Zentrum München (Múnic, Alemanya))
Prokisch, Holger (Helmholtz Zentrum München (Múnic, Alemanya))
Dols Icardo, Oriol (Institut d'Investigació Biomèdica Sant Pau)
Clarimón, Jordi (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Lleó, Alberto (Institut d'Investigació Biomèdica Sant Pau)
Santana, Isabel (University of Coimbra (Coïmbra, Portugal))
Almeida, Maria Rosário (University of Coimbra (Coïmbra, Portugal))
Santiago, Beatriz (Centro Hospitalar Universitário de Coimbra (Coïmbra, Portugal))
Heneka, Michael (University of Bonn (Bonn, Alemanya))
Jessen, Frank (University of Bonn (Bonn, Alemanya))
Ramirez, Alfredo (University of Bonn (Bonn, Alemanya))
Sanchez-Valle, Raquel (Hospital Clínic i Provincial de Barcelona)
Llado Plarrumani, Albert (Hospital Clínic i Provincial de Barcelona)
Gelpi, Ellen (Hospital Clínic i Provincial de Barcelona)
Sarafov, Stayko (Medical University Sofia (Sofia, Bulgària))
Tournev, Ivailo (New Bulgarian University (Sofia, Bulgària))
Jordanova, Albena (Medical University Sofia (Sofia, Bulgaria))
Parobkova, Eva (Thomayer Hospital (Praga, República Txeca))
Fabrizi, Gian Maria (University of Verona (Verona, Itàlia))
Testi, Silvia (University of Verona (Verona, Itàlia))
Salmon, Eric (University of Liege and Memory Clinic (Lieja, Bèlgica))
Ströbel, Thomas (Medical University of Vienna (Viena, Àustria))
Santens, Patrick (Universitair Ziekenhuis Gent (Gant, Bèlgica))
Robberecht, Wim (Vesalius Research Center Louvain (Lovaina, Bèlgica))
De Jonghe, Peter (University Hospital Antwerp (Anvers, Bèlgica))
Martin, Jean-Jacques (University of Antwerp (Anvers, Bèlgica))
Cras, Patrick (University Hospital Antwerp (Anvers, Bèlgica))
Vandenberghe, Rik (University Hospitals Gasthuisberg (Leuven, Bélgica))
De Deyn, Peter Paul (University of Groningen (Groningen, Països Baixos))
Cruts, Marc (University of Antwerp (Anvers, Bèlgica))
Sleegers, Kristel (University of Antwerp (Anvers, Bèlgica))
Van Broeckhoven, Christine (University of Antwerp (Anvers, Bèlgica))
Universitat Autònoma de Barcelona. Departament de Medicina

Date:	2014
Abstract:	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. © 2014 The Author(s).
Grants:	Ministerio de Economía y Competitividad PI12/01311
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	ALS ; FTLD ; P62 ; Rare variants ; Sequestosome 1 ; SQSTM1
Published in:	Acta Neuropathologica, Vol. 128 Núm. 3 (september 2014) , p. 397-410, ISSN 1432-0533

DOI: 10.1007/s00401-014-1298-7
PMID: 24899140

14 p, 2.5 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
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