Journal article
SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration
Brain (London, England : 1878), Vol.144(9), pp.2798-2811
10/22/2021
DOI: 10.1093/brain/awab171
PMID: 34687211
Abstract
The G(4)C(2)-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 x 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.
Details
- Title: Subtitle
- SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration
- Creators
- Mathieu Barbier - Allen Institute for Brain ScienceAgnes Camuzat - Allen Institute for Brain ScienceKhalid El Hachimi - Allen Institute for Brain ScienceJustine Guegan - Allen Institute for Brain ScienceDaisy Rinaldi - Allen Institute for Brain ScienceSerena Lattante - Università Cattolica del Sacro CuoreMarion Houot - Allen Institute for Brain ScienceRaquel Sanchez-Valle - CognITMario Sabatelli - Università Cattolica del Sacro CuoreAnna Antonell - Consorci Institut D'Investigacions Biomediques August Pi I SunyerLaura Molina-Porcel - CognITFabienne Clot - Pitié-Salpêtrière HospitalPhilippe Couratier - Ctr Demences Rares Univ Hosp Limoges, Limoges, FranceEmma van der Ende - Erasmus MCJulie van der Zee - Center for Neuro-OncologyClaudia Manzoni - UCL, Sch Pharm, London, EnglandWilliam Camu - Université de MontpellierCecile Cazeneuve - Pitié-Salpêtrière HospitalFrancois Sellal - Hopitaux Civils de ColmarMira Didic - Hôpital de la TimoneVeronique Golfier - Ctr Hosp Yves Le Foll, Serv Neurol, St Brieuc, FranceFlorence Pasquier - Université de LilleCharles Duyckaerts - Allen Institute for Brain ScienceGiacomina Rossi - Fondazione IRCCS Istituto Neurologico Carlo BestaAmalia C. Bruni - BioAgeVictoria Alvarez - Central University Hospital of AsturiasEstrella Gomez-Tortosa - Fdn Jimenez Diaz, Dept Neurol, Madrid, SpainAlexandre de Mendonca - University of LisbonCaroline Graff - Karolinska University HospitalMario Masellis - Sunnybrook HospitalBenedetta Nacmias - University of FlorenceBadreddine Mohand Oumoussa - Pitié-Salpêtrière HospitalLudmila Jornea - Allen Institute for Brain ScienceSylvie Forlani - Allen Institute for Brain ScienceViviana Van Deerlin - Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USAJonathan D. Rohrer - UCL, Dementia Res Ctr, Dept Neurodegenerat Dis, UCL Queen Sq Inst Neurol, London, EnglandEllen Gelpi - Consorci Institut D'Investigacions Biomediques August Pi I SunyerRosa Rademakers - VIB-UAntwerp Center for Molecular NeurologyJohn Van Swieten - Erasmus MCEric Le Guern - Pitié-Salpêtrière HospitalChristine Van Broeckhoven - VIB-UAntwerp Center for Molecular NeurologyRaffaele Ferrari - UCL, Inst Neurol, London, EnglandEmmanuelle Genin - Génétique, Génomique Fonctionnelle et BiotechnologiesAlexis Brice - Allen Institute for Brain ScienceIsabelle Le Ber - Allen Institute for Brain ScienceFrench clinical and genetic Research network on FTLD/FTLD-ALS and PREVDEMALS study groupInternational Frontotemporal Dementia Genomics ConsortiumEuropean Early Onset Dementia (EU -EOD) ConsortiumBrainbank Neuro-CEB Neuropathology NetworkNeurological Tissue Bank of the Biobank Hospital Clinic-IDIBAPSTimothy Griffiths (Contributor) - Psychological and Brain Sciences
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.144(9), pp.2798-2811
- Publisher
- Oxford Univ Press
- DOI
- 10.1093/brain/awab171
- PMID
- 34687211
- ISSN
- 0006-8950
- eISSN
- 1460-2156
- Number of pages
- 14
- Grant note
- ANR-11-INBS-0011 / Investissements d'avenir; Agence Nationale de la Recherche (ANR) fondi per la ricerca 2019 284 / Alzheimer's Society grant 1402 1300 / Dioraphte foundation Association pour la Recherche sur la Sclerose Laterale Amyotrophique -ARSLA Methusalem Excellence Program 20143810 / Fundacio Marato de TV3, Barcelona, Spain Bluefield Project to Cure Frontotemporal Dementia FONDATION-WES-20161202 / Fondation Maladies Rares Grant Instituto de Salud Carlos III; Spanish Government University of Antwerp Research Fund 7330550813; 733050103 / Deltaplan Dementie (the Netherlands Organisation for Health Research and Development and Alzheimer Nederland) European Joint Programme-Neurodegenerative Disease Research (JPND, PreFrontALS) FIS14/00099 / FEDER funds grant; Marie Curie Actions Flemish Government initiated Impulse Program on Networks for Dementia Research (V.I.N.D.) ANR/DGOS PREVDEMALS; Agence Nationale de la Recherche (ANR) Programme Hospitalier de Recherche Clinique (PHRC) FTLD-exome Research Foundation Flanders (F.W.O.); FWO
- Language
- English
- Date published
- 10/22/2021
- Academic Unit
- Psychological and Brain Sciences
- Record Identifier
- 9984627284502771
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