SLITRK2 , an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration
In: ISSN: 0006-8950, 2021
academicJournal
Zugriff:
International audience ; 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 ...
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SLITRK2 , an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration
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| Autor/in / Beteiligte Person: | Barbier, Mathieu ; Camuzat, Agnès ; El Hachimi, Khalid ; 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 ; 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 ; Gelpi, Ellen ; Rademakers, Rosa ; van Swieten, John ; Le Guern, Eric ; van Broeckhoven, Christine ; Ferrari, Raffaele ; Génin, Emmanuelle ; Brice, Alexis ; Le Ber, Isabelle ; 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 (MCPN) ; 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 CHU 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 Toronto (Sunnybrook) ; Università degli Studi di Firenze = University of Florence = Université de 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) ; ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011) ; ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010) |
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| Zeitschrift: | ISSN: 0006-8950, 2021 |
| Veröffentlichung: | HAL CCSD ; Oxford University Press, 2021 |
| Medientyp: | academicJournal |
| DOI: | 10.1093/brain/awab171 |
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