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9 results on '"EU EOD Consortium"'

1. TRIM25 mutation (p.C168*), coding for an E3 ubiquitin ligase, is a cause of early-onset autosomal dominant dementia with amyloid load and parkinsonism.

Author

Gómez-Tortosa E, Baradaran-Heravi Y, Dillen L, Choudhury NR, Agüero Rabes P, Pérez-Pérez J, Kocoglu C, Sainz MJ, Ruiz González A, Téllez R, Cremades-Jimeno L, Cárdaba B, Van Broeckhoven C, Michlewski G, and van der Zee J

Subjects
Humans, Codon, Nonsense, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, Amyloidogenic Proteins, Biomarkers, Tripartite Motif Proteins genetics, Transcription Factors genetics, Alzheimer Disease diagnostic imaging, Alzheimer Disease genetics, Dementia, Amyloidosis, Parkinsonian Disorders diagnostic imaging, Parkinsonian Disorders genetics
Abstract

Introduction: Patients with familial early-onset dementia (EOD) pose a unique opportunity for gene identification studies., Methods: We present the phenotype and whole-exome sequencing (WES) study of an autosomal dominant EOD family. Candidate genes were examined in a set of dementia cases and controls (n = 3712). Western blotting was conducted of the wild-type and mutant protein of the final candidate., Results: Age at disease onset was 60 years (range 56 to 63). The phenotype comprised mixed amnestic and behavioral features, and parkinsonism. Cerebrospinal fluid and plasma biomarkers, and a positron emission tomography amyloid study suggested Alzheimer's disease. WES and the segregation pattern pointed to a nonsense mutation in the TRIM25 gene (p.C168*), coding for an E3 ubiquitin ligase, which was absent in the cohorts studied. Protein studies supported a loss-of-function mechanism., Discussion: This study supports a new physiopathological mechanism for brain amyloidosis. Furthermore, it extends the role of E3 ubiquitin ligases dysfunction in the development of neurodegenerative diseases., Highlights: A TRIM25 nonsense mutation (p.C168*) is associated with autosomal dominant early-onset dementia and parkinsonism with biomarkers suggestive of Alzheimer's disease. TRIM25 protein studies support that the mutation exerts its effect through loss of function. TRIM25, an E3 ubiquitin ligase, is known for its role in the innate immune response but this is the first report of association with neurodegeneration. The role of TRIM25 dysfunction in development of amyloidosis and neurodegeneration merits a new line of research., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Published
2023
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2. Familial primary lateral sclerosis or dementia associated with Arg573Gly TBK1 mutation

Author

Christine Van Broeckhoven, Eloísa Navarro, Jesús Esteban-Pérez, Alberto García-Redondo, Ilse Gijselinck, M. José Sainz, María Ruggiero, Marc Cruts, Rosa Guerrero-López, Daniel Borrego-Hernández, Julie van der Zee, Julián Pérez-Pérez, Estrella Gómez-Tortosa, and EU EOD Consortium

Subjects
0301 basic medicine, Genetics, business.industry, Autosomal dominant trait, Frontotemporal lobar degeneration, medicine.disease, 03 medical and health sciences, Psychiatry and Mental health, 030104 developmental biology, 0302 clinical medicine, medicine, Missense mutation, Dementia, Surgery, Neurology (clinical), Human medicine, Amyotrophic lateral sclerosis, business, Index case, 030217 neurology & neurosurgery, Frontotemporal dementia, Primary Lateral Sclerosis
Abstract

Primary lateral sclerosis (PLS) is a rare variant of motor neuron disease (MND) characterised by selective upper motor neuron features whose causes and pathogenic mechanisms remain largely unknown. While some familial cases of childhood to young–adult onset with recessive transmission have been reported in association with mutations in the Alsin, SPG11 and SPG7 genes,1 most adult cases occur sporadically. Recently, Tank-binding kinase 1 ( TBK1 ) mutations have been identified in 1.9% of frontotemporal dementia(FTD) and/or Amyotrophic lateral sclerosis (ALS) cohorts.2 However, pathogenicity of many TBK1 missense mutations is difficult to establish in the absence of cosegregation data. A screening for TBK1 mutations carried out by the European Early-Onset Dementia (EU EOD) Consortium in a large series of FTD/ALS cases found one carrier of the Arg573Gly mutation.3 The index case belonged to a Spanish family with autosomal dominant disease manifesting in the sixth decade as either dementia or PLS, and in whom we were able to demonstrate cosegregation. TBK1 screening included 2553 individuals with FTD and/or ALS and 2288 European controls, including 549 of Spanish origin, and was conducted by the EU EOD Consortium as previously described.3 The family with the Arg573Gly mutation comprises an affected father and nine offspring, of whom five have been affected by either dementia or PLS (figure 1). Four affected and one healthy sibling have been clinically and genetically examined. Retrospective information was obtained regarding the disease process in cases I.1 and II. 2. Figure 1 Top: family tree. Bottom: sequence of recruitment of clinical features in the affected family members. Amnestic dementia refers to …

Published
2017

3. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration

Author

Barbier, Mathieu, Camuzat, Agnès, Hachimi, Khalid El, Guegan, Justine, Rinaldi, Daisy, Lattante, Serena, Houot, Marion, Sánchez-Valle, Raquel, Sabatelli, Mario, Antonell, Anna, Molina-Porcel, Laura, Clot, Fabienne, Couratier, Philippe, van der Ende, Emma, van der Zee, Julie, Manzoni, Claudia, Camu, William, Cazeneuve, Cécile, Sellal, François, Didic, Mira, Golfier, Véronique, Pasquier, Florence, Duyckaerts, Charles, Rossi, Giacomina, Bruni, Amalia C, Alvarez, Victoria, Gómez-Tortosa, Estrella, de Mendonça, Alexandre, Graff, Caroline, Masellis, Mario, Nacmias, Benedetta, Oumoussa, Badreddine Mohand, Jornea, Ludmila, Forlani, Sylvie, Van Deerlin, Viviana, Rohrer, Jonathan D, Gelpi, Ellen, Rademakers, Rosa, Van Swieten, John, Le Guern, Eric, Van Broeckhoven, Christine, Ferrari, Raffaele, Génin, Emmanuelle, Brice, Alexis, Ber, Le, Isabelle Alexis Brice, Sophie, Auriacombe, Serge, Belliard, Anne, Bertrand, Anne, Bissery, Fre ́ de, ́ ric Blanc, Marie-Paule, Boncoeur, Ste, ́ phanie Bombois, Claire Boutoleau-Bretonnie` re, Agne`, s Camuzat, Mathieu, Ceccaldi, Marie, Chupin, Philippe, Couratier, Olivier, Colliot, Vincent, Deramecourt, Mira, Didic, Bruno, Dubois, Charles, Duyckaerts, Fre ́ de, ́ rique Etcharry-Bouyx, Aure, ́ lie Guignebert-Funkiewiez, Maı ̈te, ́ Formaglio, ́ ronique Golfier, Ve, Marie-Odile, Habert, Didier, Hannequin, Lucette, Lacomblez, Julien, Lagarde, ́ raldine Lautrette, Ge, Isabelle Le Ber, Benjamin Le Toullec, Richard, Levy, Marie-Anne, Mackowiak, Bernard-Franc ̧ois Michel, Florence, Pasquier, Thibaud, Lebouvier, Carole Roue, ́ -Jagot, Christel Thauvin- Robinet, Catherine, Thomas-Anterion, Je ́ re, ́ mie Pariente, Franc ̧ois Salachas, Sabrina, Sayah, Franc ̧ois Sellal, Assi-Herve, ́ Oya, Daisy, Rinaldi, Adeline, Rollin-Sillaire, Martine, Vercelletto, David, Wallon, Armelle, Rametti-Lacroux, Raffaele, Ferrari, Hernandez, Dena G., Nalls, Michael A., Rohrer, Jonathan D., Adaikalavan, Ramasamy, Kwok, John B. J., Carol Dobson- Stone, Brooks, William S., Schofield, Peter R., Halliday, Glenda M., Hodges, John R., Olivier, Piguet, Lauren, Bartley, Elizabeth, Thompson, Isabel Herna, ́ ndez, Agustı ́n Ruiz, Merce`, Boada, Barbara, Borroni, Alessandro, Padovani, Carlos, Cruchaga, Cairns, Nigel J., Luisa, Benussi, Giuliano, Binetti, Roberta, Ghidoni, Gianluigi, Forloni, Diego, Albani, Daniela, Galimberti, Chiara, Fenoglio, Maria, Serpente, Elio, Scarpini, ́ n, Jordi Clarimo, Alberto Lleo, ́, Rafael, Blesa, Maria Landqvist Waldo, ̈, Karin, Nilsson, Christer, Nilsson, Mackenzie, Ian R. A., Hsiung, Ging-Yuek R., Mann, David M. A., Jordan, Grafman, Morris, Christopher M., Johannes, Attems, Griffiths, Timothy D., Mckeith, Ian G., Thomas, Alan J., Pietro, Pietrini, Edward, Uey, Wassermann, Eric M., Atik, Baborie, Evelyn, Jaros, Tierney, Michael C., Pau, Pastor, Cristina, Razquin, Sara, Ortega-Cubero, Elena, Alonso, Robert, Perneczky, Janine, Diehl-Schmid, Panagiotis, Alexopoulos, Alexander, Kurz, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Ekaterina, Rogaeva, Peter St George-Hyslop, Giacomina, Rossi, Fabrizio, Tagliavini, Giorgio, Giaccone, Rowe, James B., Schlachetzki, Johannes C. M., James, Uphill, John, Collinge, Simon, Mead, Adrian, Danek, Van Deerlin, Vivianna M., Murray, Grossman, Trojanowski, John Q., Julie van der Zee, Christine Van Broeckhoven, Cappa, Stefano F., Isabelle, Leber, Alexis, Brice, Benedetta, Nacmias, Sandro, Sorbi, Silvia, Bagnoli, Irene, Piaceri, Nielsen, Jørgen E., Hjermind, Lena E., Matthias, Riemenschneider, Manuel, Mayhaus, Bernd, Ibach, Gilles, Gasparoni, Sabrina, Pichler, Wei, Gu, Rossor, Martin N., Fox, Nick C., Warren, Jason D., Maria Grazia Spillantini, Morris, Huw R., Patrizia, Rizzu, Peter, Heutink, Snowden, Julie S., Sara, Rollinson, Anna, Richardson, Alexander, Gerhard, Bruni, Amalia C., Raffaele, Maletta, Francesca, Frangipane, Chiara, Cupidi, Livia, Bernardi, Maria, Anfossi, Maura, Gallo, Maria Elena Conidi, Nicoletta, Smirne, Rosa, Rademakers, Matt, Baker, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., David, Knopman, Josephs, Keith A., Boeve, Bradley F., Parisi, Joseph E., Seeley, William W., Miller, Bruce L., Karydas, Anna M., Howard, Rosen, van Swieten, John C., Dopper, Elise G. P., Harro, Seelaar, Pijnenburg, Yolande A. L., Philip, Scheltens, Giancarlo, Logroscino, Rosa, Capozzo, Valeria, Novelli, Puca, Annibale A., Massimo, Franceschi, Alfredo, Postiglione, Graziella, Milan, Paolo, Sorrentino, Mark, Kristiansen, Huei-Hsin, Chiang, Caroline, Graff, Adeline, Rollin, Dimitrios, Kapogiannis, Luigi, Ferrucci, Stuart, Pickering-Brown, Singleton, Andrew B., John, Hardy, Parastoo, Momeni., Neurology, Amsterdam Neuroscience - Neurodegeneration, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Dupuytren [CHU Limoges], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Center for Molecular Neurology (VIB-UAntwerp), University of Antwerp (UA), University College of London [London] (UCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Yves le Foll, Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Hospital Central de Asturias, Institute of Health Research of Principado de Asturias (ISPA), Fundación Jiménez Díaz, Fundacion Jimenez Diaz [Madrid] (FJD), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA), Karolinska University Hospital [Stockholm], Sunnybrook Research Institute [Toronto] (SRI), Sunnybrook Health Sciences Centre, Università degli Studi di Firenze = University of Florence (UniFI), Fondazione Don Carlo Gnocchi, Plateforme Post-génomique de la Pitié-Salpêtrière (PASS-P3S), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania, Neurodegenerative Brain Diseases group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), The French clinical and genetic Research network on FTLD/FTLD-ALS and PREVDEMALS, The International Frontotemporal Dementia Genomics Consortium, The European Early Onset Dementia (EU -EOD) Consortium, Brainbank Neuro-CEB Neuropathology Network, and Neurological Tissue Bank of the Biobank Hospital Clinic-IDIBAPS

Subjects
Adult, Male, TDP-43, C9orf72, SLITRK2, amyotrophic lateral sclerosis, frontotemporal dementia, Nerve Tissue Proteins, Settore MED/03 - GENETICA MEDICA, Polymorphism, Single Nucleotide, Cohort Studies, Genes, X-Linked, 80 and over, Medicine, Dementia, Humans, Allele, Age of Onset, Polymorphism, Aged, Aged, 80 and over, biology, C9orf72 Protein, business.industry, Membrane Proteins, MESH: Frontotemporal Lobar Degeneration / epidemiology, Frontotemporal Lobar, Degeneration / genetics, Genes, X-Linked / genetics, Genome-Wide Association Study / methods, Frontotemporal lobar degeneration, Single Nucleotide, Middle Aged, X-Linked, medicine.disease, Amyotrophic lateral sclerosis, Minor allele frequency, Genes, Immunology, Synaptophysin, biology.protein, Female, MESH: Adult, C9orf72 Protein / genetics, Frontotemporal Lobar Degeneration / diagnosis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, Neurology (clinical), MESH: Humans, Membrane Proteins / genetics, Nerve Tissue Proteins / genetics, Polymorphism, Single Nucleotide / genetics, Age of onset, Frontotemporal Lobar Degeneration, business, Frontotemporal dementia, Genome-Wide Association Study
Abstract

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10−5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

Published
2021
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4. Familial primary lateral sclerosis or dementia associated with Arg573Gly TBK1 mutation.

Author

Gómez-Tortosa, Estrella, Van Der Zee, Julie, Ruggiero, María, Gijselinck, Ilse, Esteban-Pérez, Jesús, García-Redondo, Alberto, Borrego-Hernández, Daniel, Navarro, Eloísa, Sainz, M. José, Pérez-Pérez, Julián, Cruts, Marc, Van Broeckhoven, Christine, and Guerrero-López, Rosa

Subjects
AMYOTROPHIC lateral sclerosis, DEMENTIA, MOTOR neuron diseases, NEUROBEHAVIORAL disorders, GENES
Published
2017
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5. Neuroimaging Correlates of Frontotemporal Dementia Associated with SQSTM1 Mutations.

Author

Luis, Elkin, Ortiz, Alexandra, Eudave, Luis, Ortega-Cubero, Sara, Borroni, Barbara, van der Zee, Julie, Gazzina, Stefano, Caroppo, Paola, Rubino, Elisa, D'Agata, Federico, Le Ber, Isabelle, Santana, Isabel, Cunha, Gil, Almeida, Maria R., Boutoleau-Bretonnièrex, Claire, Hannequin, Didier, Wallon, David, Rainero, Innocenzo, Galimberti, Daniela, and Van Broeckhoven, Christine

Subjects
BRAIN imaging, FRONTOTEMPORAL dementia, FRONTOTEMPORAL lobar degeneration, GENETIC mutation, MORPHOMETRICS, DIAGNOSIS
Abstract

Background: Frontotemporal lobar degeneration (FTLD) is a progressive dementia characterized by focal atrophy of frontal and/or temporal lobes caused by mutations in the gene coding for sequestosome 1 (SQSTM1), among other genes. Rare SQSTM1 gene mutations have been associated with Paget's disease of bone, amyotrophic lateral sclerosis, and, more recently, frontotemporal lobar degeneration (FTLD).Objective: The aim of the study was to determine whether a characteristic pattern of grey and white matter loss is associated with SQSTM1 dysfunction.Methods: We performed a voxel-based morphometry (VBM) study in FTD subjects carrying SQSTM1 pathogenic variants (FTD/SQSTM1 mutation carriers; n = 10), compared with FTD subjects not carrying SQSTM1 mutations (Sporadic FTD; n = 20) and healthy controls with no SQSTM1 mutations (HC/SQSTM1 noncarriers; n = 20). The groups were matched according to current age, disease duration, and gender.Results: After comparing FTD/SQSTM1 carriers with Sporadic FTD, a predominantly right cortical atrophy pattern was localized in the inferior frontal, medial orbitofrontal, precentral gyri, and the anterior insula. White matter atrophy was found in both medial and inferior frontal gyri, pallidum, and putamen. FTD/SQSTM1 carriers compared with HC/SQSTM1 noncarriers showed atrophy at frontal, temporal, and parietal lobes of both hemispheres whereas the MRI pattern found in Sporadic FTD compared with controls was frontal and left temporal lobe atrophy, extending toward parietal and occipital lobes of both hemispheres.Conclusions: These results suggest that fronto-orbito-insular regions including corticospinal projections as described in ALS are probably more susceptible to the damaging effect of SQSTM1 mutations delineatinga specific gene-linked atrophy pattern. [ABSTRACT FROM AUTHOR]

Published
2016
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6. A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease.

Author

Verheijen, Jan, Bossche, Tobi, Zee, Julie, Engelborghs, Sebastiaan, Sanchez-Valle, Raquel, Lladó, Albert, Graff, Caroline, Thonberg, Håkan, Pastor, Pau, Ortega-Cubero, Sara, Pastor, Maria, Benussi, Luisa, Ghidoni, Roberta, Binetti, Giuliano, Clarimon, Jordi, Lleó, Alberto, Fortea, Juan, Mendonça, Alexandre, Martins, Madalena, and Grau-Rivera, Oriol

Subjects
ALZHEIMER'S disease, GENETICS, DEMENTIA, GENETIC code, MICROBIAL virulence
Abstract

The sortilin-related receptor 1 ( SORL1) gene has been associated with increased risk for Alzheimer's disease (AD). Rare genetic variants in the SORL1 gene have also been implicated in autosomal dominant early-onset AD (EOAD). Here we report a large-scale investigation of the contribution of genetic variability in SORL1 to EOAD in a European EOAD cohort. We performed massive parallel amplicon-based re-sequencing of the full coding region of SORL1 in 1255 EOAD patients and 1938 age- and origin-matched control individuals in the context of the European Early-Onset Dementia (EOD) consortium, originating from Belgium, Spain, Portugal, Italy, Sweden, Germany, and Czech Republic. We identified six frameshift variants and two nonsense variants that were exclusively present in patients. These mutations are predicted to result in haploinsufficiency through nonsense-mediated mRNA decay, which could be confirmed experimentally for SORL1 p.Gly447Argfs*22 observed in a Belgian EOAD patient. We observed a 1.5-fold enrichment of rare non-synonymous variants in patients (carrier frequency 8.8 %; SkatOMeta p value 0.0001). Of the 84 non-synonymous rare variants detected in the full patient/control cohort, 36 were only detected in patients. Our findings underscore a role of rare SORL1 variants in EOAD, but also show a non-negligible frequency of these variants in healthy individuals, necessitating the need for pathogenicity assays. Premature stop codons due to frameshift and nonsense variants, have so far exclusively been found in patients, and their predicted mode of action corresponds with evidence from in vitro functional studies of SORL1 in AD. [ABSTRACT FROM AUTHOR]

Published
2016
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7. Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration.

Author

Zee, Julie, Langenhove, Tim, Kovacs, Gabor, Dillen, Lubina, Deschamps, William, Engelborghs, Sebastiaan, Matěj, Radoslav, Vandenbulcke, Mathieu, Sieben, Anne, Dermaut, Bart, Smets, Katrien, Damme, Philip, Merlin, Céline, Laureys, Annelies, Broeck, Marleen, Mattheijssens, Maria, Peeters, Karin, Benussi, Luisa, Binetti, Giuliano, and Ghidoni, Roberta

Subjects
AMYOTROPHIC lateral sclerosis, DEGENERATION (Pathology), BRAIN degeneration, DEMENTIA, NEUROMUSCULAR diseases, ALLELES
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. [ABSTRACT FROM AUTHOR]

Published
2014
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8. TARDBP mutation p. Ile383 Val associated with semantic dementia and complex proteinopathy.

Author

Gelpi, E., Zee, J., Turon Estrada, A., Van Broeckhoven, C., and Sanchez‐Valle, R.

Subjects
TEMPORAL lobe diseases, NEUROLOGICAL disorders, GENETIC mutation, DEMENTIA, ATROPHY, AMYOTROPHIC lateral sclerosis, GENETICS
Abstract

The article presents a neuropathological study of a 60-year-old man with frontotemporal lobar degenerations (FTLD) to determine the correlation of TARDBP mutation p.Ile383Val with semantic dementia and complex proteinopathy. The study investigates the temporally accentuated atrophy. The study concludes that the presence of p.Ile383Val mutation in TARDBP indicates a complex clinico-genetic-neuropathological relationships within the continuum FTLD-amyotrophic lateral sclerosis (ALS).

Published
2014
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9. Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia

Author

Albert Lladó, Jordi Clarimón, Barbara Borroni, Roberta Ghidoni, Rik Vandenberghe, Giovanni B. Frisoni, Isabel Santana, Alberto Lleó, Sara Van Mossevelde, Christiana Willems, Benedetta Nacmias, Mathieu Vandenbulcke, Mercè Boada, Adrian Ivanoiu, Giuliano Binetti, Maria Rosário Almeida, Peter Paul De Deyn, Marc Cruts, Monica Diez-Fairen, Miquel Aguilar, Anne Sieben, Marleen Van den Broeck, Gabriel Miltenberger-Miltenyi, Eline Wauters, Christine Van Broeckhoven, Patrick Cras, Raquel Sánchez-Valle, Estrella Gómez-Tortosa, Sandro Sorbi, Isabel Hernández, Ellen Gelpi, Agustín Ruiz, Julie van der Zee, Lubina Dillen, Alexandre de Mendonça, Luisa Benussi, Karin Peeters, Sebastiaan Engelborghs, Alessandro Padovani, Pau Pastor, Stéphanie Philtjens, Frisoni, Giovanni, Repositório da Universidade de Lisboa, BELNEU Consortium, EU EOD Consortium, Physiotherapy, Human Physiology and Anatomy, Clinical sciences, Neurology, and Pathologic Biochemistry and Physiology

Subjects
0301 basic medicine, Nonsynonymous substitution, Male, Aging, Geriatrics & Gerontology, Granulin, AMYOTROPHIC-LATERAL-SCLEROSIS, Cohort Studies, 0302 clinical medicine, Progranulins, Belgium, Medicine(all), Genetics, PLASMA, General Neuroscience, Adaptor Proteins, Vesicular Transport/chemistry, Middle Aged, Europe, Genetic Variation/genetics, Intercellular Signaling Peptides and Proteins, Female, Frontotemporal dementia, Genetic association, Rare variants, Sortilin, Life Sciences & Biomedicine, Cohort study, Protein Binding, Risk, Neuroscience(all), DIAGNOSTIC-CRITERIA, Clinical Neurology, PROGRANULIN LEVELS, C9ORF72, Biology, 03 medical and health sciences, Protein Domains, Genetic variation, mental disorders, medicine, Dementia, Humans, BELGIAN COHORT, Adaptor Proteins, Vesicular Transport/chemistry/genetics, LOBAR DEGENERATION, Gene, Genetic Association Studies, Aged, Science & Technology, HEXANUCLEOTIDE REPEAT, Binding Sites, MUTATIONS, Neurosciences, Genetic Variation, medicine.disease, Ageing, Adaptor Proteins, Vesicular Transport, 030104 developmental biology, ddc:618.97, Human medicine, Neurology (clinical), Neurosciences & Neurology, Geriatrics and Gerontology, 030217 neurology & neurosurgery, Developmental Biology
Abstract

© 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/), We investigated the genetic role of sortilin (SORT1) in frontotemporal dementia (FTD). SORT1 is the neuronal receptor for granulin, encoded by the progranulin gene (GRN), a major causal gene for inherited FTD. In Belgian cohorts of 636 FTD patients and 1066 unaffected control individuals, we identified 5 patient-only nonsynonymous rare variants in SORT1. Rare variant burden analysis showed a significant increase in rare coding variants in patients compared to control individuals (p = 0.04), particularly in the β-propeller domain (p = 0.04), with 2 rare variants located in the predicted binding site for GRN (p = 0.001). We extended these observations by analyzing 3 independent patient/control cohorts sampled in Spain, Italy, and Portugal by partners of the European Early-Onset Dementia Consortium, together with 1155 FTD patients and 1161 control persons. An additional 7 patient-only nonsynonymous variants were observed in SORT1 in European patients. Meta-analysis of the rare nonsynonymous variants in the Belgian and European patient/control cohorts revealed a significant enrichment in FTD patients (p = 0.006), establishing SORT1 as a genetic risk factor for FTD., The research was funded in part by the Belgian Science Policy Office Interuniversity Attraction Poles program; the Flemish government initiated Methusalem excellence program and Impulse Program on Networks for Dementia Research; the Research Foundation Flanders (FWO), the Agency for Innovation by Science and Technology Flanders (IWT) and the University of Antwerp Research Fund; Belgium. SP received a PhD fellowship of the FWO and EW of the IWT. RG, LB, and GB (IRCCS Fatebenefratelli, Brescia, Italy) were supported by Ricerca Corrente, Italian Ministry of Health.

Published
2018

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