Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration

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 d...

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Main 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
Format:	Online
Language:	English
Published:	Springer Berlin Heidelberg 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131163/

id	pubmed-4131163
recordtype	oai_dc
spelling	pubmed-41311632014-08-14 Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration 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 Original Paper 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. Springer Berlin Heidelberg 2014-06-05 2014 /pmc/articles/PMC4131163/ /pubmed/24899140 http://dx.doi.org/10.1007/s00401-014-1298-7 Text en © The Author(s) 2014 Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	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
spellingShingle	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 Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration
author_facet	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
author_sort	van der Zee, Julie
title	Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration
title_short	Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration
title_full	Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration
title_fullStr	Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration
title_full_unstemmed	Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration
title_sort	rare mutations in sqstm1 modify susceptibility to frontotemporal lobar degeneration
description	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.
publisher	Springer Berlin Heidelberg
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131163/
_version_	1613123721570025472

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration

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