Title: Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration
Authors: van der Zee, Julie ×
Van Langenhove, Tim
Kovacs, Gabor G
Dillen, Lubina
Deschamps, William
Engelborghs, Sebastiaan
Matěj, Radoslav
Vandenbulcke, Mathieu
Sieben, Anne
Dermaut, Bart
Smets, Katrien
Van Damme, Philip
Merlin, Céline
Laureys, Annelies
Van Den Broeck, Marleen
Mattheijssens, Maria
Peeters, Karin
Benussi, Luisa
Binetti, Giuliano
Ghidoni, Roberta
Borroni, Barbara
Padovani, Alessandro
Archetti, Silvana
Pastor, Pau
Razquin, Cristina
Ortega-Cubero, Sara
Hernández, Isabel
Boada, Mercè
Ruiz, Agustín
de Mendonça, Alexandre
Miltenberger-Miltényi, Gabriel
do Couto, Frederico Simões
Sorbi, Sandro
Nacmias, Benedetta
Bagnoli, Silvia
Graff, Caroline
Chiang, Huei-Hsin
Thonberg, Håkan
Perneczky, Robert
Diehl-Schmid, Janine
Alexopoulos, Panagiotis
Frisoni, Giovanni B
Bonvicini, Christian
Synofzik, Matthis
Maetzler, Walter
Vom Hagen, Jennifer Müller
Schöls, Ludger
Haack, Tobias B
Strom, Tim M
Prokisch, Holger
Dols-Icardo, Oriol
Clarimón, Jordi
Lleó, Alberto
Santana, Isabel
Almeida, Maria Rosário
Santiago, Beatriz
Heneka, Michael T
Jessen, Frank
Ramirez, Alfredo
Sanchez-Valle, Raquel
Llado, Albert
Gelpi, Ellen
Sarafov, Stayko
Tournev, Ivailo
Jordanova, Albena
Parobkova, Eva
Fabrizi, Gian Maria
Testi, Silvia
Salmon, Eric
Ströbel, Thomas
Santens, Patrick
Robberecht, Wim
De Jonghe, Peter
Martin, Jean-Jacques
Cras, Patrick
Vandenberghe, Rik
De Deyn, Peter Paul
Cruts, Marc
Sleegers, Kristel
Van Broeckhoven, Christine #
Issue Date: Sep-2014
Publisher: Springer Verlag
Series Title: Acta Neuropathologica vol:128 issue:3 pages:397-410
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.
ISSN: 0001-6322
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Neurobiology (Vesalius Research Center)
Research Group Psychiatry
Laboratory for Cognitive Neurology
× corresponding author
# (joint) last author

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