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Open Access 01-09-2014 | Original Paper

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration

Authors: Julie van der Zee, Tim Van Langenhove, Gabor G. Kovacs, Lubina Dillen, William Deschamps, Sebastiaan Engelborghs, Radoslav Matěj, Mathieu Vandenbulcke, Anne Sieben, Bart Dermaut, Katrien Smets, Philip Van Damme, Céline Merlin, Annelies Laureys, Marleen Van Den Broeck, Maria Mattheijssens, Karin Peeters, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Barbara Borroni, Alessandro Padovani, Silvana Archetti, Pau Pastor, Cristina Razquin, Sara Ortega-Cubero, Isabel Hernández, Mercè Boada, Agustín Ruiz, Alexandre de Mendonça, Gabriel Miltenberger-Miltényi, Frederico Simões do Couto, Sandro Sorbi, Benedetta Nacmias, Silvia Bagnoli, Caroline Graff, Huei-Hsin Chiang, Håkan Thonberg, Robert Perneczky, Janine Diehl-Schmid, Panagiotis Alexopoulos, Giovanni B. Frisoni, Christian Bonvicini, Matthis Synofzik, Walter Maetzler, Jennifer Müller vom Hagen, Ludger Schöls, Tobias B. Haack, Tim M. Strom, Holger Prokisch, Oriol Dols-Icardo, Jordi Clarimón, Alberto Lleó, Isabel Santana, Maria Rosário Almeida, Beatriz Santiago, Michael T. Heneka, Frank Jessen, Alfredo Ramirez, Raquel Sanchez-Valle, Albert Llado, Ellen Gelpi, Stayko Sarafov, Ivailo Tournev, Albena Jordanova, Eva Parobkova, Gian Maria Fabrizi, Silvia Testi, Eric Salmon, Thomas Ströbel, Patrick Santens, Wim Robberecht, Peter De Jonghe, Jean-Jacques Martin, Patrick Cras, Rik Vandenberghe, Peter Paul De Deyn, Marc Cruts, Kristel Sleegers, Christine Van Broeckhoven

Published in: Acta Neuropathologica | Issue 3/2014

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.

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Title: Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration
Authors: Julie van der Zee
Tim Van Langenhove
Gabor G. Kovacs
Lubina Dillen
William Deschamps
Sebastiaan Engelborghs
Radoslav Matěj
Mathieu Vandenbulcke
Anne Sieben
Bart Dermaut
Katrien Smets
Philip Van Damme
Céline Merlin
Annelies Laureys
Marleen Van Den Broeck
Maria Mattheijssens
Karin Peeters
Luisa Benussi
Giuliano Binetti
Roberta Ghidoni
Barbara Borroni
Alessandro Padovani
Silvana Archetti
Pau Pastor
Cristina Razquin
Sara Ortega-Cubero
Isabel Hernández
Mercè Boada
Agustín Ruiz
Alexandre de Mendonça
Gabriel Miltenberger-Miltényi
Frederico Simões do Couto
Sandro Sorbi
Benedetta Nacmias
Silvia Bagnoli
Caroline Graff
Huei-Hsin Chiang
Håkan Thonberg
Robert Perneczky
Janine Diehl-Schmid
Panagiotis Alexopoulos
Giovanni B. Frisoni
Christian Bonvicini
Matthis Synofzik
Walter Maetzler
Jennifer Müller vom Hagen
Ludger Schöls
Tobias B. Haack
Tim M. Strom
Holger Prokisch
Oriol Dols-Icardo
Jordi Clarimón
Alberto Lleó
Isabel Santana
Maria Rosário Almeida
Beatriz Santiago
Michael T. Heneka
Frank Jessen
Alfredo Ramirez
Raquel Sanchez-Valle
Albert Llado
Ellen Gelpi
Stayko Sarafov
Ivailo Tournev
Albena Jordanova
Eva Parobkova
Gian Maria Fabrizi
Silvia Testi
Eric Salmon
Thomas Ströbel
Patrick Santens
Wim Robberecht
Peter De Jonghe
Jean-Jacques Martin
Patrick Cras
Rik Vandenberghe
Peter Paul De Deyn
Marc Cruts
Kristel Sleegers
Christine Van Broeckhoven
Publication date: 01-09-2014
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 3/2014
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-014-1298-7

At a glance: The STEP trials

Springer Medicine

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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