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2. SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration
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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
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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.
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- 2021
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3. Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia
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Eliecer Coto, Pau Pastor, Maria Serpente, Sandro Sorbi, Benedetta Nacmias, Victoria Alvarez, Raffaele Maletta, Livia Bernardi, Sergio Pérez-Oliveira, Paola Caroppo, Roberta Ghidoni, Manuel Menéndez-González, Irene Piaceri, Raffaele Ferrari, Beatriz De la Casa-Fages, Daniela Galimberti, Raquel Sánchez-Valle, Monica Diez-Fairen, Oriol Dols-Icardo, Ignacio Illán-Gala, Ifgc, Daniel Queimaliños-Perez, Elio Scarpini, Julie van der Zee, Amalia C. Bruni, Christine Van Broeckhoven, Maria Rosário Almeida, Giacomina Rossi, Irene Rosas, Carmen Martínez, Silvia Bagnoli, Francisco Grandas, Barbara Borroni, Jordi Clarimón, Alberto Lleó, Giuliano Binetti, Luisa Benussi, Anna Antonell, Maria Anfossi, and EU EOD Consortium
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0301 basic medicine ,Apolipoprotein E ,Male ,Aging ,Heterozygote ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Apolipoproteins E ,Progranulins ,C9orf72 ,mental disorders ,Genetic variation ,medicine ,Humans ,TP53 ,Gene ,Genetic Association Studies ,Genetics ,Heterogeneous group ,C9orf72 Protein ,Age at onset ,APOE ,Frontotemporal dementia ,GRN ,Survival probability ,General Neuroscience ,Genetic Variation ,medicine.disease ,Phenotype ,030104 developmental biology ,Disease risk ,Female ,Human medicine ,Neurology (clinical) ,Geriatrics and Gerontology ,Tumor Suppressor Protein p53 ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials.
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- 2021
4. No supportive evidence for TIA1 gene mutations in a European cohort of ALS-FTD spectrum patients
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Ellen Gelpi, Mathieu Vandenbulcke, Yalda Baradaran-Heravi, Alex Michotte, Alexandre de Mendonça, Elisa Bonomi, Peter Paul De Deyn, Peter Heutink, Bruno Bergmans, Matthew J. Fraidakis, Matthis Synofzik, Dirk Peeters, Eva Parobkova, Christine Van Broeckhoven, Patrick Santens, Peter De Jonghe, Radoslav Matej, Maria Rosário Almeida, Rik Vandenberghe, Hung Phuoc Nguyen, Pau Pastor, Alessandro Padovani, Gabriel Miltenberger-Miltenyi, Jan De Bleecker, Philip Van Damme, Sara Van Mossevelde, Isabel Santana, Ricard Rojas-García, Olivier Deryck, Julie van der Zee, Eric Salmon, Ana Verdelho, Christiana Willems, Nina De Klippel, Miquel Aguilar, Lubina Dillen, Alberto Lleó, Sergi Borrego-Écija, Sebastiaan Engelborghs, Sandro Sorbi, Jonathan Baets, Camilla Ferrari, Monica Diez-Fairen, Silvia Bagnoli, Barbara Borroni, Raquel Sánchez-Valle, Johan Goeman, Anne Sieben, Ignacio Illán-Gala, Patrick Cras, Panagiotis Alexopoulos, Janina Turon-Sans, Benedetta Nacmias, Adrian Ivanoiu, Irene Piaceri, Janine Diehl-Schmid, Jan Versijpt, Silvana Archettim, C. Ferreira, Frederico Simões do Couto, Jordi Clarimón, Dirk Nuytten, Javier Simón-Sánchez, Carlo Wilke, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, BELNEU Consortium1, EU EOD Consortium, Clinical sciences, Neurology, and Pathologic Biochemistry and Physiology
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0301 basic medicine ,Oncology ,Male ,Aging ,Geriatrics & Gerontology ,Gene mutation ,Frontotemporal dementia (FTD) ,AMYOTROPHIC-LATERAL-SCLEROSIS ,Pathogenesis ,Cohort Studies ,0302 clinical medicine ,Gene Frequency ,Medicine and Health Sciences ,Missense mutation ,Amyotrophic lateral sclerosis (ALS) ,Amyotrophic lateral sclerosis ,genetics [Frontotemporal Dementia] ,Medicine(all) ,General Neuroscience ,ddc ,genetics [Amyotrophic Lateral Sclerosis] ,genetics [European Continental Ancestry Group] ,Frontotemporal Dementia ,Cohort ,T cellerestricted intracellular antigen-1 gene (TIA1) ,Female ,Life Sciences & Biomedicine ,Cohort study ,Frontotemporal dementia ,medicine.medical_specialty ,European Continental Ancestry Group ,genetics [White People] ,Mutation, Missense ,White People ,03 medical and health sciences ,Internal medicine ,mental disorders ,medicine ,Humans ,ddc:610 ,genetics [T-Cell Intracellular Antigen-1] ,Biology ,Allele frequency ,T cell–restricted intracellular antigen-1 gene (TIA1) ,Science & Technology ,business.industry ,TIA1 protein, human ,Amyotrophic Lateral Sclerosis ,Neurosciences ,TAR DNA-Binding protein 43 (TDP-43) ,FRONTOTEMPORAL DEMENTIA ,medicine.disease ,T-Cell Intracellular Antigen-1 ,030104 developmental biology ,Human medicine ,Neurology (clinical) ,Neurosciences & Neurology ,Geriatrics and Gerontology ,business ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
We evaluated the genetic contribution of the T cell-restricted intracellular antigen-1 gene (TIA1) in a European cohort of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients. Exonic resequencing of TIA1 in 1120 patients (693 FTD, 341 ALS, 86 FTD-ALS) and 1039 controls identified in total 5 rare heterozygous missense variants, affecting the TIA1 low-complexity domain (LCD). Only 1 missense variant, p.Met290Thr, identified in a familial FTD patient with disease onset at 64 years, was absent from controls yet received a combined annotation-dependent depletion score of 11.42. By contrast, 3 of the 4 variants also detected in unaffected controls, p.Val294Glu, p.Gln318Arg, and p.Ala381Thr, had combined annotation-dependent depletion scores greater than 20. Our findings in a large European patient-control series indicate that variants in TIA1 are not a common cause of ALS and FTD. The observation of recurring TIA1 missense variants in unaffected individuals lead us to conclude that the exact genetic contribution of TIA1 to ALS and FTD pathogenesis remains to be further elucidated. ispartof: NEUROBIOLOGY OF AGING vol:69 ispartof: location:United States status: published
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- 2018
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5. Presence of tau astrogliopathy in frontotemporal dementia caused by a novel Grn nonsense (Trp2*) mutation
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María José Sainz, Alberto Rábano Gutiérrez, Cristina Prieto-Jurczynska, Estrella Gómez-Tortosa, Yalda Baradaran-Heravi, Christine Van Broeckhoven, Valentina González Alvarez, Julie van der Zee, Rosa Guerrero-López, Pablo Agüero Rabes, and EU EOD Consortium
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0301 basic medicine ,Proband ,Male ,Aging ,Pathology ,medicine.medical_specialty ,Nonsense mutation ,tau Proteins ,Neuropathology ,Biology ,Temporal lobe ,03 medical and health sciences ,0302 clinical medicine ,Progranulins ,mental disorders ,medicine ,Subependymal zone ,Humans ,Genetic Association Studies ,Aged ,Genes, Dominant ,Aged, 80 and over ,General Neuroscience ,Brain ,Neurofibrillary Tangles ,Frontotemporal lobar degeneration ,Middle Aged ,medicine.disease ,030104 developmental biology ,Tauopathies ,Codon, Nonsense ,Astrocytes ,Frontotemporal Dementia ,Female ,Neurology (clinical) ,Tauopathy ,Human medicine ,Geriatrics and Gerontology ,030217 neurology & neurosurgery ,Developmental Biology ,Frontotemporal dementia - Abstract
Frontotemporal lobar degeneration caused by GRN mutations is mainly associated with a TDP-43 type A proteinopathy. We present a family with autosomal dominant frontotemporal lobar degeneration caused by a novel GRN nonsense mutation (c.5G>A: p.Trp2*) in which the proband's brain also showed prominent glial tauopathy consistent with an aging-related tau astrogliopathy. Astrocytic tauopathy, 4R(+) and 3R(-) immunoreactive, was characterized by thorn-shaped astrocytes present in subpial, subependymal, and perivascular areas, and in gray matter; plus granular or fuzzy tau immunoreactivity in astrocytic processes in gray matter, either solitary or clustered in different regions. Some neurofibrillary tangles and pretangles, both 3R and 4R(+), were present in the medial temporal lobe but did not exhibit the characteristic distribution of Alzheimer's type pathology. This 4R-tau aging-related tau astrogliopathy is likely a co-occurring pathology, although an interaction between progranulin and tau proteins within the neurodegenerative process should not be ruled out.
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- 2018
6. Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia
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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
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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.
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- 2018
7. Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort
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Juan Fortea, Marc Cruts, Tobi Van den Bossche, Jan Versijpt, Alessandro Padovani, Luisa Benussi, Roberta Ghidoni, Alexandre de Mendonça, Elena Lorenzo, Manuel Seijo-Martínez, Jaume Campdelacreu, Sandro Sorbi, Radoslav Matej, Peter Paul De Deyn, Panagiotis Alexopoulos, Olivier Deryck, Albert Lladó, Pau Pastor, Frederico Simões do Couto, Rik Vandenberghe, Estrella Gómez-Tortosa, Zdenek Rohan, Jordi Clarimón, Anne Sieben, Jordi Gascon, Isabel Santana, Maria A. Pastor, Maria Koutroumani, Madalena Martins, Sebastiaan Engelborghs, Janine Diehl-Schmid, Christine Van Broeckhoven, Benedetta Nacmias, Patrick Santens, Lubina Dillen, Ilse Gijselinck, Giuliano Binetti, Silvia Bagnoli, Bruno Bergmans, Agustín Ruiz, Raquel Sánchez-Valle, Barbara Borroni, Maria Rosário Almeida, Kristel Sleegers, Ellen Gelpi, Adrian Ivanoiu, Bavo Heeman, Cristina Razquin, Magda Tsolaki, Elena Iglesias, Caroline Graff, Johan Goeman, Alberto Lleó, Valentina Bessi, Laura Fratiglioni, Jan Verheijen, Alex Michotte, Jan De Bleecker, Rafael Blesa, Julie van der Zee, Eric Salmon, Ramón Reñé, Dirk Nuytten, Mathieu Vandenbulcke, Bart Dermaut, Håkan Thonberg, Christiana Willems, BELNEU Consortium, EU EOD Consortium, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service de neurologie, Clinical sciences, Neurology, and Pathologic Biochemistry and Physiology
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0301 basic medicine ,Oncology ,Male ,Aging ,TBK1 ,Early onset Alzheimer's disease ,Frontotemporal dementia ,Loss-of-function ,RNA sequencing ,Neuroscience (all) ,Neurology (clinical) ,Developmental Biology ,Geriatrics and Gerontology ,Disease ,Bioinformatics ,medicine.disease_cause ,AMYOTROPHIC-LATERAL-SCLEROSIS ,Loss of Function Mutation/genetics ,Cohort Studies ,Frontotemporal Dementia/genetics ,0302 clinical medicine ,Loss of Function Mutation ,Medicine and Health Sciences ,Early-onset Alzheimer's disease ,Family history ,Amyotrophic lateral sclerosis ,Medicine(all) ,Mutation ,General Neuroscience ,Homozygote ,Amyotrophic Lateral Sclerosis/genetics ,Middle Aged ,Protein-Serine-Threonine Kinases ,3. Good health ,ddc ,Europe ,Genetic Variation/genetics ,Frontotemporal Dementia ,Cohort ,Female ,Risk ,medicine.medical_specialty ,Heterozygote ,BINDING KINASE 1 ,Protein-Serine-Threonine Kinases/genetics ,Neuroscience(all) ,Clinical Neurology ,IMMUNITY ,Biology ,Protein Serine-Threonine Kinases ,03 medical and health sciences ,Early onset Alzheimer’s disease ,Alzheimer Disease ,Internal medicine ,medicine ,Humans ,BELGIAN COHORT ,Loss function ,Alleles ,Genetic Association Studies ,Aged ,Alzheimer Disease/genetics ,MUTATIONS ,Amyotrophic Lateral Sclerosis ,Biology and Life Sciences ,Genetic Variation ,medicine.disease ,Ageing ,030104 developmental biology ,Human medicine ,030217 neurology & neurosurgery - Abstract
TANK-binding kinase 1 (TBK1) loss-of-function (LoF) mutations are known to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), often combined with memory deficits early in the disease course. We performed targeted resequencing of TBK1 in 1253 early onset Alzheimer's disease (EOAD) patients from 8 European countries to investigate whether pathogenic TBK1 mutations are enriched among patients with clinical diagnosis of EOAD. Variant frequencies were compared against 2117 origin-matched controls. We identified only 1 LoF mutation (p.Thr79del) in a patient clinically diagnosed with Alzheimer's disease and a positive family history of ALS. We did not observe enrichment of rare variants in EOAD patients compared to controls, nor of rare variants affecting NFκB induction. Of 3 common coding variants, rs7486100 showed evidence of association (OR 1.46 [95% CI 1.13-1.9]; p-value 0.01). Homozygous carriers of the risk allele showed reduced expression of TBK1 (p-value 0.03). Our findings are not indicative of a significant role for TBK1 mutations in EOAD. The association between common variants in TBK1, disease risk and reduced TBK1 expression warrants follow-up in FTD/ALS cohorts. ispartof: Neurobiology of Aging vol:62 pages:245- ispartof: location:United States status: published
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- 2018
8. Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer's disease
- Author
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Peter Paul De Deyn, Kristel Sleegers, Raquel Sánchez-Valle, Ellen Gelpi, Zdenek Rohan, Isabel Santana, Julie van der Zee, Patrick Cras, Panagiotis Alexopoulos, Madalena Martins, A. Lleo, Håkan Thonberg, Alessandro Padovani, Giuliano Binetti, Sandro Sorbi, Albert Lladó, Sebastiaan Engelborghs, Bavo Heeman, Tobi Van den Bossche, Alexandre de Mendonça, Pau Pastor, Christine Van Broeckhoven, Arne De Roeck, Maria Koutroumani, Janine Diehl-Schmid, Maria Rosário Almeida, Juan Fortea, Jasper Van Dongen, Sara Ortega-Cubero, Roberta Ghidoni, Lubina Dillen, Oriol Grau-Rivera, Estrella Gómez-Tortosa, Luisa Benussi, Maria A. Pastor, Benedetta Nacmias, Wouter De Coster, Caroline Graff, Jordi Clarimón, Magda Tsolaki, Jan Verheijen, Yalda Baradaran-Heravi, Barbara Borroni, Radoslav Matěj, European Early-Onset Dementia, Clinical sciences, Neurology, Physiotherapy, Human Physiology and Anatomy, Pathologic Biochemistry and Physiology, and European Early-Onset Dementia (EU EOD) consortium
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0301 basic medicine ,Adult ,Male ,endocrine system diseases ,ATP-Binding Cassette Transporters/genetics ,Early Onset Alzheimer’s disease ,Member 7 (ABCA7) ,Biology ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,Pathology and Forensic Medicine ,ABCA7 ,Loss-of-function ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Third-generation long-read sequencing ,Alzheimer Disease ,medicine ,Coding region ,Humans ,Early-onset Alzheimer's disease ,Genetic Predisposition to Disease ,Age of Onset ,Modifier ,Gene ,Genetic Association Studies ,Aged ,Medicine(all) ,Genetics ,Alzheimer Disease/genetics ,Mutation ,Original Paper ,Sub-Family A ,Alternative splicing ,RNA sequencing ,Middle Aged ,medicine.disease ,Penetrance ,3. Good health ,030104 developmental biology ,biology.protein ,Early Onset Alzheimer's disease ,ATP-Binding Cassette Transporters ,Female ,ATP-Binding Cassette ,Neurology (clinical) ,Human medicine ,Age of onset - Abstract
Altres ajuts: The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The research was funded in part by the European Commission Seventh Framework Programme for research, technological development, and demonstration under grant agreement 305299 (AgedBrainSYSBIO), the Belgian Science Policy Office Interuniversity Attraction Poles program, the Alzheimer Research Foundation (SAO-FRA), the Flemish government-initiated Flanders Impulse Program on Networks for Dementia Research (VIND), the Flemish government-initiated Methusalem Excellence Program, the Research Foundation Flanders (FWO), the VIB Technology Fund, the University of Antwerp Research Fund, Belgium; European Regional Development Fund, the Italian Ministry of Health (Ricerca Corrente and RF-2010-2319722), and the Fondazione Cassa di Risparmio di Pistoia e Pescia grant (2014.0365). Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD.
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- 2017
9. Familial primary lateral sclerosis or dementia associated with Arg573Gly TBK1 mutation
- Author
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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
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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
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