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8 results on '"Isabelle, Leber"'

1. A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors

Author

Imogen J. Swift, Rosa Rademakers, NiCole Finch, Matt Baker, Roberta Ghidoni, Luisa Benussi, Giuliano Binetti, Giacomina Rossi, Matthis Synofzik, Carlo Wilke, David Mengel, Caroline Graff, Leonel T. Takada, Raquel Sánchez-Valle, Anna Antonell, Daniela Galimberti, Chiara Fenoglio, Maria Serpente, Marina Arcaro, Stefanie Schreiber, Stefan Vielhaber, Philipp Arndt, Isabel Santana, Maria Rosario Almeida, Fermín Moreno, Myriam Barandiaran, Alazne Gabilondo, Johannes Stubert, Estrella Gómez-Tortosa, Pablo Agüero, M. José Sainz, Tomohito Gohda, Maki Murakoshi, Nozomu Kamei, Sarah Kittel-Schneider, Andreas Reif, Johannes Weigl, Jinlong Jian, Chuanju Liu, Ginette Serrero, Thomas Greither, Gerit Theil, Ebba Lohmann, Stefano Gazzina, Silvia Bagnoli, Giovanni Coppola, Amalia Bruni, Mirja Quante, Wieland Kiess, Andreas Hiemisch, Anne Jurkutat, Matthew S. Block, Aaron M. Carlson, Geir Bråthen, Sigrid Botne Sando, Gøril Rolfseng Grøntvedt, Camilla Lauridsen, Amanda Heslegrave, Carolin Heller, Emily Abel, Alba Gómez-Núñez, Roger Puey, Andrea Arighi, Enmanuela Rotondo, Lize C. Jiskoot, Lieke H. H. Meeter, João Durães, Marisa Lima, Miguel Tábuas-Pereira, João Lemos, Bradley Boeve, Ronald C. Petersen, Dennis W. Dickson, Neill R. Graff-Radford, Isabelle LeBer, Leila Sellami, Foudil Lamari, Fabienne Clot, Barbara Borroni, Valentina Cantoni, Jasmine Rivolta, Alberto Lleó, Juan Fortea, Daniel Alcolea, Ignacio Illán-Gala, Lucie Andres-Cerezo, Philip Van Damme, Jordi Clarimon, Petra Steinacker, Emily Feneberg, Markus Otto, Emma L. van der Ende, John C. van Swieten, Harro Seelaar, Henrik Zetterberg, Aitana Sogorb-Esteve, and Jonathan D. Rohrer

Subjects
Frontotemporal dementia, Progranulin, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. Methods Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. Results We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. Conclusions These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.

Published
2024
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2. Brain dysfunction in gait disorders of Caribbean atypical Parkinsonism and progressive supranuclear palsy patients: A comparative study

Author

Marie-Laure Welter, Alexandre Vasseur, Regine Edragas, Hugo Chaumont, Fanny Pineau, Graziella Mangone, Claire Olivier, Isabelle Leber, Sophie Rivaud-Pechoux, Stéphane Lehericy, Cecile Gallea, Lydia Yahia-Cherif, and Annie Lannuzel

Subjects
Gait disorders, Progressive supranuclear palsy, Caribean atypical parkinsonism, Gait recordings, Magnetic resonance imaging, Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract

Introduction: Gait disorders and falls occur early in progressive supranuclear palsy (PSP-RS) and Caribbean atypical parkinsonism (Caribbean AP). However, the link between these signs and brain lesions has never been explored in these patient populations. Here, we investigate and compare the imaging factors that relate to gait and balance disorders in Caribbean AP and PSP-RS patients. Methods: We assessed gait and balance using clinical scales and gait recordings in 16 Caribbean AP and 15 PSP-RS patients and 17 age-matched controls. We measured the grey and white matter brain volumes on 3 T brain MRI images. We performed a principal component analysis (PCA) including all the data to determine differences and similarities between groups, and explore the relationship between gait disorders and brain volumes. Results: Both Caribbean AP patients and PSP-RS have marked gait and balance disorders with similar severity. In both groups, gait and balance disorders were found to be most strongly related to structural changes in the lateral cerebellum, caudate nucleus, and fronto-parietal areas. In Caribbean AP patients, gait disorders were also related to additional changes in the cortex, including frontal, insular, temporal and cuneus lobes, whereas in PSP-RS patients, additional white matter changes involved the mesencephalon and parahippocampal gyrus. Conclusion: Gait and balance disorders in Caribbean AP patients are mainly related to dysfunction of cortical brain areas involved in visuo-sensorimotor processing and self-awareness, whereas these signs mainly result from premotor-brainstem-cerebellar network dysfunction in PSP-RS patients, brain areas involved in initiation and maintenance of locomotor pattern and postural adaptation.

Published
2023
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3. The European Reference Network for Rare Neurological Diseases

Author

Carola Reinhard, Anne-Catherine Bachoud-Lévi, Tobias Bäumer, Enrico Bertini, Alicia Brunelle, Annemieke I. Buizer, Antonio Federico, Thomas Gasser, Samuel Groeschel, Sanja Hermanns, Thomas Klockgether, Ingeborg Krägeloh-Mann, G. Bernhard Landwehrmeyer, Isabelle Leber, Alfons Macaya, Caterina Mariotti, Wassilios G. Meissner, Maria Judit Molnar, Jorik Nonnekes, Juan Dario Ortigoza Escobar, Belen Pérez Dueñas, Lori Renna Linton, Ludger Schöls, Rebecca Schuele, Marina A. J. Tijssen, Rik Vandenberghe, Anna Volkmer, Nicole I. Wolf, and Holm Graessner

Subjects
rare neurological diseases, standards of care, training and education, virtual healthcare, European reference network, Neurology. Diseases of the nervous system, RC346-429
Abstract

While rare diseases (RDs) are by definition of low prevalence, the total number of patients suffering from an RD is high, and the majority of them have neurologic manifestations, involving central, peripheral nerve, and muscle. In 2017, 24 European Reference Networks (ERNs), each focusing on a specific group of rare or low-prevalence complex diseases, were formed to improve the care for patients with an RD. One major aim is to have “the knowledge travel instead of the patient,” which has been put into practice by the implementation of the Clinical Patient Management System (CPMS) that enables clinicians to perform pan-European virtual consultations. The European Reference Network for Rare Neurological Diseases (ERN-RND) provides an infrastructure for knowledge sharing and care coordination for patients affected by a rare neurological disease (RND) involving the most common central nervous system pathological conditions. It covers the following disease groups: (i) Cerebellar Ataxias and Hereditary Spastic Paraplegias; (ii) Huntington's disease and Other Choreas; (iii) Frontotemporal dementia; (iv) Dystonia, (non-epileptic) paroxysmal disorders, and Neurodegeneration with Brain Iron Accumulation; (v) Leukoencephalopathies; and (vi) Atypical Parkinsonian Syndromes. At the moment, it unites 32 expert centers and 10 affiliated partners in 21 European countries, as well as patient representatives, but will soon cover nearly all countries of the European Union as a result of the ongoing expansion process. Disease expert groups developed and consented on diagnostic flowcharts and disease scales to assess the different aspects of RNDs. ERN-RND has started to discuss diagnostically unclear patients in the CPMS, is one of four ERNs that serve as foundation of Solve-RD, and has established an RND training and education program. The network will facilitate trial readiness through the establishment of an ERN-RND registry with a minimal data of all patients seen at the ERN-RND centers, thus providing a unique overview of existing genotype-based cohorts. The overall aim of the ERNs is to improve access for patients with RDs to quality diagnosis, care, and treatment. Based on this objective, ERNs are monitored by the European Commission on a regular basis to provide transparency and reassurance to the RD community and the general public.

Published
2021
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4. Association study of the GAB2 gene with the risk of developing Alzheimer's disease

Author

Julien Chapuis, Didier Hannequin, Florence Pasquier, Peter Bentham, Alexis Brice, Isabelle Leber, Thierry Frebourg, Jean-François Deleuze, Emmanuelle Cousin, Uma Thaker, Philippe Amouyel, David Mann, Corinne Lendon, Dominique Campion, and Jean-Charles Lambert

Subjects
Alzheimer, GAB2, APOE, Polymorphism, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

The first genome-wide association in Alzheimer's disease (AD) suggested that the GAB2 gene rs2373115 polymorphism may be a strong risk factor in APOE ɛ4-carriers. We failed to detect an association of rs2373115 with the risk of developing AD in three populations (totalling 1406 controls and 1749 AD cases) whatever the APOE status, even if we observed a slight tendency for an increase of the GG genotype (OR (GG versus GT+TT)=1.3, 95% CI 1.0–1.6, p=0.09) and the G allele frequency (OR=1.3, 95%CI 1.0–1.6, p=0.05) in ɛ4-carriers. In addition, the rs2373115 did not modulate the extent of tau phosphorylation in the brain of 89 AD cases. The GAB2 gene is at best a minor genetic determinant of AD.

Published
2008
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5. 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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6. Identification of common variants influencing risk of the tauopathy Progressive Supranuclear Palsy

Author

Marla Gearing, Jean Paul G. Vonsattel, Anna Karydas, Manuela Apfelbacher, Herbert Budka, Bernie Devlin, Alessandro Padovani, Wallace W. Tourtellotte, Andrew J. Lees, Karin Srulijes, Li-San Wang, Klaus Seppi, Gianni Pezzoli, Yvette Bordelon, Claudia Trenkwalder, Ryan J. Uitti, Peter Paul De Deyn, Nicole A. Finch, Roger L. Albin, Ranjan Duara, Gerard D. Schellenberg, Alberto Rábano, Kelly E. Lyons, Rosa Rademakers, Douglas Galasko, Giorgio Sacilotto, Dennis W. Dickson, Günter U. Höglinger, Silvana Tesei, John Hardy, Carlo Colosimo, Eliezer Masliah, Pia Winter, Joseph Jankovic, William W. Seeley, Claudio Mariani, David E. Riley, Matthew J. Farrer, Angelo Antonini, Jens Carsten Möller, Alex Rajput, Hans A. Kretzschmar, Nenad Bogdanovic, Nadine M. Melhem, Ulrich Müller, Steven E. Arnold, Wolfgang H. Oertel, Jorge L. Juncos, Rachel G. Gross, Daniela Berg, Rajesh Pahwa, Deborah A. Hall, Alexandra Durr, Chris Zarow, Lili-Naz Hazrati, Virginia M.-Y. Lee, Justo Garcãa De Yebenes, Donatella Ottaviani, John C. van Swieten, Tamas Revesz, John Q. Trojanowski, Zbigniew K. Wszolek, Sigrun Roeber, Werner Poewe, Matthias Höllerhage, Neill R. Graff-Radford, Laura B. Cantwell, Elena Alonso, Irene Litvan, Claire Troakes, Patrick M. A. Sleiman, Peter St George-Hyslop, Isabelle Leber, Lawrence I. Golbe, Chang En Yu, Allissa Dillman, Anna Zecchinelli, Stephen G. Reich, Stefano Goldwurm, Salvatore Spina, Eduardo Tolosa, Vivianna M. Van Deerlin, Charles L. White, Agnita J.W. Boon, Andrew B. Singleton, Huw R. Morris, Mi Ryung Han, Dena G. Hernandez, Carles Gaig, Matthew P. Frosch, Sebastiaan Engelborghs, Juan C. Troncoso, Roberto Cilia, Catriona McLean, Thomas Gasser, Robyn Flook, Barbara Borroni, Rohan de Silva, Murray Grossman, Martin N. Rossor, Bruce L. Miller, Sean S. O'Sullivan, Hakon Hakonarson, Walter Maetzler, Thomas D. Bird, David G. Standaert, Gesine Respondek, Marcel P. van der Brug, Sherry Beecher, Howard I. Hurtig, Gregor K. Wenning, J. Raphael Gibbs, Alexis Brice, Stuart Pickering-Brown, Jonathan D. Rohrer, Christopher Morris, Jana Vandrovcova, Giovanni Fabbrini, Jesús Avila, Owen A. Ross, Margherita Canesi, Lambertus Klei, Andrew P. Lieberman, Bernardino Ghetti, Laura Silveira-Moriyama, Peter Heutink, Pau Pastor, Nicoletta Meucci, Evan T. Geller, Luke A. Massey, Wang Zheng Chiu, Laura Donker Kaat, Maria Stamelou, Brit Mollenhauer, Mark R. Cookson, Thomas G. Beach, Novartis, Federal Ministry of Education and Research (Germany), Helmholtz Association, European Commission, Human genetics, NCA - Neurodegeneration, Neurology, Foundation for the National Institutes of Health, National Institute of Mental Health (US), German Genomics Initiative, German Research Foundation, Medical Research Council (UK), NIHR Biomedical Research Centre (UK), Harvard Brain Tissue Resource Center, Telethon Italia, Canadian Institutes of Health Research, Mayo Clinic, Nafarroako Gobernua, Fondazione Grigioni per il Morbo di Parkinson, De Deyn, Peter Paul, Engelborghs, Sebastiaan, and PSP Genetics Study Group

Subjects
pathology [Tauopathies], Genome-wide association study, Neurodegenerative, Medical and Health Sciences, Cohort Studies, 0302 clinical medicine, Degenerative disease, Risk Factors, Corticobasal degeneration, GWAS, 2.1 Biological and endogenous factors, Supranuclear Palsy, Chromosomes, Human, EIF2AK3, Aetiology, Genetics, Pediatric, 0303 health sciences, genetics [Supranuclear Palsy, Progressive], Single Nucleotide, Biological Sciences, Prognosis, 3. Good health, Frontotemporal Dementia (FTD), Tauopathies, Neurological, genetics [Polymorphism, Single Nucleotide], Tauopathy, Brain diseases, Supranuclear Palsy, Progressive, Palsy, Human, pathology [Supranuclear Palsy, Progressive], Single-nucleotide polymorphism, MAPT protein, human, tau Proteins, Neuropathology, Progressive Supranuclear Palsy, Biology, genetics [Chromosomes, Human], Polymorphism, Single Nucleotide, Chromosomes, Article, Progressive supranuclear palsy, PSP Genetics Study Group, 03 medical and health sciences, Rare Diseases, Progressive, ddc:570, medicine, Acquired Cognitive Impairment, Humans, Genetic Predisposition to Disease, Polymorphism, 030304 developmental biology, Cerebral Palsy, Prevention, Human Genome, genetics [Tauopathies], Neurosciences, Genetic Variation, Perinatal Period - Conditions Originating in Perinatal Period, medicine.disease, eye diseases, Brain Disorders, genetics [tau Proteins], Genetic Loci, Case-Control Studies, Dementia, Human medicine, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common being Alzheimer’s disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 PSP cases and 3,247 controls (Stage 1) followed up by a second stage where 1,051 cases and 3,560 controls were genotyped for Stage 1 SNPs that yielded P ≤ 10−3. We found significant novel signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3, and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response, and for a myelin structural component., T.G. serves as an editorial board member of Movement Disorders and Parkinsonism and Related Disorders and is funded by Novartis Pharma, the Federal Ministry of Education and Research (BMBF) (NGFN-Plus and ERA-Net NEURON), the Helmholtz Association (HelMA, Helmholtz Alliance for Health in an Ageing Society) and the European Community (MeFoPa, Medndelian Forms of Parkinsonism). T.G. received speakers honoraria from Novartis, Merck-Serono, Schwarz Pharma, Boehringer Ingelheim and Valeant Pharma and royalties for his consulting activities from Cefalon Pharma and Merck-Serono. T.G. holds a patent concerning the LRRK2 gene and neurodegenerative disorders. J.H. is consulting for Merck Serono and Eisai. I.Litvan is the founder of the Litvan Neurological Research Foundation, whose mission is to increase awareness, determine the cause/s and search for a cure for neurodegenerative disorders presenting with either parkinsonian or dementia symptoms (501c3).

Published
2011
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7. MISSENSE MUTATIONS IN THE AFG3L2 PROTEOLYTIC DOMAIN ACCOUNT FOR ~1.5% OF EUROPEAN AUTOSOMAL DOMINANT CEREBELLAR ATAXIAS

Author

Luisa Pugliese, Marcello Nobili, Corrado Assalto, Russell L. Margolis, Pascale Ribai, Nicola Migone, Claudia Cagnoli, Sylvie Forlani, Patrizia Pappi, Giovanni Stevanin, Alessandro Brussino, Isabelle Leber, Alexis Brice, Susan E. Holmes, Sergio Padovan, Marco Barberis, Alexandra Durr, Alfredo Brusco, Cécile Zaros, Cecilia Mancini, Genetics Biology and Biochemistry, University of Turin, Polytech'Paris-UPMC, Université Pierre et Marie Curie - Paris 6 (UPMC), Johns Hopkins University School of Medicine [Baltimore], Division of Neurology, Martini Hospital, CNR Istituto Di Biostrutture E Bioimmagini (IBB-CNR), Consiglio Nazionale delle Ricerche [Torino] (CNR), SAFAN bioinformatics, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Genetics Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), CNR Istituto di biostrutture e bioimmagini [ Napoli] (CNR | IBB), National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), and Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Male, Models, Molecular, Adolescent, Cerebellar Ataxia, Mutation, Missense, Biology, medicine.disease_cause, White People, 03 medical and health sciences, Exon, Young Adult, 0302 clinical medicine, Autosomal dominant cerebellar ataxia, ATP-Dependent Proteases, Genetics, medicine, Prevalence, Missense mutation, Humans, Spinocerebellar Ataxias, Child, Gene, Genetics (clinical), 030304 developmental biology, Aged, Genes, Dominant, Spinocerebellar Degenerations, 0303 health sciences, Mutation, Cerebellar ataxia, Point mutation, Computational Biology, Infant, Life Sciences, Middle Aged, medicine.disease, Molecular biology, 3. Good health, Pedigree, Europe, Child, Preschool, Spinocerebellar ataxia, ATPases Associated with Diverse Cellular Activities, Female, medicine.symptom, 030217 neurology & neurosurgery
Abstract

Spinocerebellar ataxia type 28 is an autosomal dominant form of cerebellar ataxia (ADCA) caused by mutations in AFG3L2, a gene that encodes a subunit of the mitochondrial m-AAA protease. We screened 366 primarily Caucasian ADCA families, negative for the most common triplet expansions, for point mutations in AFG3L2 using DHPLC. Whole-gene deletions were excluded in 300 of the patients, and duplications were excluded in 129 patients. We found six missense mutations in nine unrelated index cases (9/366, 2.6%): c.1961C>T (p.Thr654Ile) in exon 15, c.1996A>G (p.Met666Val), c.1997T>G (p.Met666Arg), c.1997T>C (p.Met666Thr), c.2011G>A (p.Gly671Arg), and c.2012G>A (p.Gly671Glu) in exon 16. All mutated amino acids were located in the C-terminal proteolytic domain. In available cases, we demonstrated the mutations segregated with the disease. Mutated amino acids are highly conserved, and bioinformatic analysis indicates the substitutions are likely deleterious. This investigation demonstrates that SCA28 accounts for ∼3% of ADCA Caucasian cases negative for triplet expansions and, in extenso, to ∼1.5% of all ADCA. We further confirm both the involvement of AFG3L2 gene in SCA28 and the presence of a mutational hotspot in exons 15–16. Screening for SCA28, is warranted in patients who test negative for more common SCAs and present with a slowly progressive cerebellar ataxia accompanied by oculomotor signs. Hum Mutat 31:1–8, 2010. © 2010 Wiley-Liss, Inc.

Published
2010
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8. Association study of the GAB2 gene with the risk of developing Alzheimer's disease

Author

Corinne Lendon, Jean-François Deleuze, U. Thaker, Thierry Frebourg, Florence Pasquier, Peter Bentham, Philippe Amouyel, Jean-Charles Lambert, David M. A. Mann, Emmanuelle Cousin, Didier Hannequin, Julien Chapuis, Isabelle Leber, Alexis Brice, and Dominique Campion

Subjects
Apolipoprotein E, Cross-Cultural Comparison, Male, Risk, medicine.medical_specialty, Genotype, Apolipoprotein E4, GAB2, Disease, Biology, Bioinformatics, lcsh:RC321-571, Gene Frequency, Polymorphism (computer science), Alzheimer Disease, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Polymorphism, Risk factor, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Gene, Allele frequency, Adaptor Proteins, Signal Transducing, Aged, Aged, 80 and over, Chi-Square Distribution, Polymorphism, Genetic, Brain, Endocrinology, Neurology, Case-Control Studies, Alzheimer, biology.protein, Female, APOE
Abstract

The first genome-wide association in Alzheimer's disease (AD) suggested that the GAB2 gene rs2373115 polymorphism may be a strong risk factor in APOE ɛ4-carriers. We failed to detect an association of rs2373115 with the risk of developing AD in three populations (totalling 1406 controls and 1749 AD cases) whatever the APOE status, even if we observed a slight tendency for an increase of the GG genotype (OR (GG versus GT + TT) = 1.3, 95% CI 1.0–1.6, p = 0.09) and the G allele frequency (OR = 1.3, 95%CI 1.0–1.6, p = 0.05) in ɛ4-carriers. In addition, the rs2373115 did not modulate the extent of tau phosphorylation in the brain of 89 AD cases. The GAB2 gene is at best a minor genetic determinant of AD.

Published
2007

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