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1.  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
Acta Neuropathologica  2014;128(3):397-410.
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.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-014-1298-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s00401-014-1298-7
PMCID: PMC4131163  PMID: 24899140
Sequestosome 1; SQSTM1; p62; FTLD; ALS; Rare variants
2.  The amyloid-β isoform pattern in cerebrospinal fluid in familial PSEN1 M139T- and L286P-associated Alzheimer's disease 
Molecular Medicine Reports  2012;5(4):1111-1115.
There are several familial forms of Alzheimer's disease (AD) most of which are caused by mutations in the genes that encode the presenilin enzymes involved in the production of amyloid-β (Aβ) from the amyloid precursor protein (APP). In AD, Aβ forms fibrils that are deposited in the brain as plaques. Much of the fibrillar Aβ found in the plaques consists of the 42 amino acid form of Aβ (Aβ1-–2) and it is now widely accepted that Aβ is related to the pathogenesis of AD and that Aβ may both impair memory and be neurotoxic. In human cerebrospinal fluid (CSF) several C- and N-terminally truncated Aβ isoforms have been detected and their relative abundance pattern is thought to reflect the production and clearance of Aβ. By using immunoprecipitation and mass spectrometry, we have previously demonstrated that carriers of the familial AD (FAD)-associated PSEN1 A431E mutation have low CSF levels of C-terminally truncated Aβ isoforms shorter than Aβ1-40. Here we replicate this finding in symptomatic carriers of the FAD-causing PSEN1 L286P mutation. Furthermore, we show that preclinical carriers of the PSEN1 M139T mutation may overexpress Aβ1-42 suggesting that this particular mutation may cause AD by stimulating γ-secretase-mediated cleavage at amino acid 42 in the Aβ sequence.
doi:10.3892/mmr.2012.774
PMCID: PMC3493058  PMID: 22307680
familial Alzheimer's; mass spectrometry; presenilin; amyloid-β isoforms
3.  Cerebrospinal fluid biomarker supported diagnosis of Creutzfeldt–Jakob disease and rapid dementias: a longitudinal multicentre study over 10 years 
Brain  2012;135(10):3051-3061.
To date, cerebrospinal fluid analysis, particularly protein 14-3-3 testing, presents an important approach in the identification of Creutzfeldt–Jakob disease cases. However, one special point of criticism of 14-3-3 testing is the specificity in the differential diagnosis of rapid dementia. The constant observation of increased cerebrospinal fluid referrals in the national surveillance centres over the last years raises the concern of declining specificity due to higher number of cerebrospinal fluid tests performed in various neurological conditions. Within the framework of a European Community supported longitudinal multicentre study (‘cerebrospinal fluid markers’) we analysed the spectrum of rapid progressive dementia diagnoses, their potential influence on 14-3-3 specificity as well as results of other dementia markers (tau, phosphorylated tau and amyloid-β1–42) and evaluated the specificity of 14-3-3 in Creutzfeldt–Jakob disease diagnosis for the years 1998–2008. A total of 29 022 cerebrospinal fluid samples were analysed for 14-3-3 protein and other cerebrospinal fluid dementia markers in patients with rapid dementia and suspected Creutzfeldt–Jakob disease in the participating centres. In 10 731 patients a definite diagnosis could be obtained. Protein 14-3-3 specificity was analysed for Creutzfeldt–Jakob disease with respect to increasing cerebrospinal fluid tests per year and spectrum of differential diagnosis. Ring trials were performed to ensure the comparability between centres during the reported time period. Protein 14-3-3 test specificity remained high and stable in the diagnosis of Creutzfeldt–Jakob disease during the observed time period across centres (total specificity 92%; when compared with patients with definite diagnoses only: specificity 90%). However, test specificity varied with respect to differential diagnosis. A high 14-3-3 specificity was obtained in differentiation to other neurodegenerative diseases (95–97%) and non-neurological conditions (91–97%). We observed lower specificity in the differential diagnoses of acute neurological diseases (82–87%). A marked and constant increase in cerebrospinal fluid test referrals per year in all centres did not influence 14-3-3 test specificity and no change in spectrum of differential diagnosis was observed. Cerebrospinal fluid protein 14-3-3 detection remains an important test in the diagnosis of Creutzfeldt–Jakob disease. Due to a loss in specificity in acute neurological events, the interpretation of positive 14-3-3 results needs to be performed in the clinical context. The spectrum of differential diagnosis of rapid progressive dementia varied from neurodegenerative dementias to dementia due to acute neurological conditions such as inflammatory diseases and non-neurological origin.
doi:10.1093/brain/aws238
PMCID: PMC3470713  PMID: 23012332
rapid dementia; Creutzfeldt–Jakob disease; cerebrospinal fluid; 14-3-3; specificity; neurodegeneration; differential diagnosis in dementia

Results 1-3 (3)