Dataset Information

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration.

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.

SUBMITTER: van der Zee J

PROVIDER: S-EPMC4131163 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration.

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

Acta neuropathologica 20140605 3

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 ...[more]

PMID: 24899140

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Project description:ObjectiveTo identify clinicopathological differences between frontotemporal lobar degeneration (FTLD) due to mutations in progranulin (FTLD-GRN) and chromosome 9 open reading frame 72 (FTLD-C9ORF72).MethodsWe performed quantitative neuropathologic comparison of 17 FTLD-C9ORF72 and 15 FTLD-GRN with a focus on microglia. For clinical comparisons, only cases with high quality medical documentation and concurring diagnoses by at least two neurologists were included (14 FTLD-GRN and 13 FTLD-C9ORF72). Neuropathological analyses were limited to TDP-43 Type A to assure consistent assessment between the groups, acknowledging that Type A is a minority of C9ORF72 patients. Furthermore, only cases with sufficient tissue from all regions were studied (11 FTLD-GRN and 11 FTLD-C9ORF72). FTLD cases were also compared to age- and sex-matched normal controls. Immunohistochemistry was performed for pTDP-43, IBA-1, CD68, and GFAP. Morphological characterization of microglia was performed in sections of cortex blinded to clinical and genetic information.ResultsFTLD-GRN patients had frequent asymmetric clinical features, including aphasia and apraxia, as well as more asymmetric cortical atrophy. Neuropathologically, FTLD-C9ORF72 had greater hippocampal tau pathology and more TDP-43 neuronal cytoplasmic inclusions. FTLD-GRN had more neocortical microvacuolation, as well as more IBA-1-positive ameboid microglia in superficial cortical layers and in subcortical white matter. FTLD-GRN also had more microglia with nuclear condensation, possibly indicating apoptosis. Microglial morphology with CD68 immunohistochemistry in FTLD-GRN and FTLD-C9ORF72 differed from controls.InterpretationOur findings underscore differences in microglial response in FTLD-C9ORF72 and FTLD-GRN as shown by significant differences in ameboid microglia in gray and white matter. These results suggest the differential contribution of microglial dysfunction in FTLD-GRN and FTLD-C9ORF72 and suggest that clinical, neuroimaging and pathologic differences could in part be related to differences in microglia response.

Dataset Information

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration.

Publications

Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration.

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