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van der Zee, J.* ; van Langenhove, T.* ; Kovacs, G.G.* ; Dillen, L.* ; Deschamps, W.* ; Engelborghs, S.* ; Matěj, R.* ; Vandenbulcke, M.* ; Sieben, A.* ; Dermaut, B.* ; Smets, K.* ; van Damme, P.V.* ; Merlin, C.* ; Laureys, A.* ; van den Broeck, M.V.* ; Mattheijssens, M.* ; Peeters, K.* ; Benussi, L.* ; Binetti, G.* ; Ghidoni, R.* ; Borroni, B.* ; Padovani, A.* ; Archetti, S.* ; Pastor, P.* ; Razquin, C.* ; Ortega-Cubero, S.* ; Hernández, I.* ; Boada, M.* ; Ruiz, A.* ; de Mendonca, A.* ; Miltenberger-Miltényi, G.* ; do Couto, F.S.* ; Sorbi, S.* ; Nacmias, B.* ; Bagnoli, S.* ; Graff, C.* ; Chiang, H.* ; Thonberg, H.* ; Perneczky, R.* ; Diehl-Schmid, J.* ; Alexopoulos, P.* ; Frisoni, G.B.* ; Bonvicini, C.* ; Synofzik, M.* ; Maetzler, W.* ; Vom Hagen, J.M.* ; Schöls, L.* ; Haack, T.B. ; Strom, T.M. ; Prokisch, H. ; Dols-Icardo, O.* ; Clarimõn, J.* ; Lleõ, A.* ; Santana, I.* ; Almeida, M.R.* ; Santiago, B.* ; Heneka, M.T.* ; Jessen, F.* ; Ramirez, A.* ; Sánchez-Valle, R.* ; Lladó, A.* ; Gelpi, E.* ; Sarafov, S.* ; Tournev, I.* ; Jordanova, A.* ; Parobková, E.* ; Fabrizi, G.M.* ; Testi, S.* ; Salmon, E.* ; Ströbel, T.* ; Santens, P.* ; Robberecht, W.* ; de Jonghe, P.* ; Martín, J.J.R.* ; Cras, P.* ; Vandenberghe, R.R.C.* ; de Deyn, P.P.* ; Cruts, M.* ; Sleegers, K.* ; van Broeckhoven, C.L.*

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration.

Acta Neuropathol. 128, 397-410 (2014)
Publ. Version/Full Text Volltext DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Als ; Ftld ; P62 ; Rare Variants ; Sequestosome 1 ; Sqstm1
ISSN (print) / ISBN 0001-6322
e-ISSN 1432-0533
Journal Acta Neuropathologica
Quellenangaben Volume: 128, Issue: 3, Pages: 397-410 Article Number: , Supplement: ,
Publisher Springer
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)