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1. 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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2. Mutational mechanism for DAB1 (ATTTC) n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution

Author

Cristina Costa, Paula Coutinho, Carolina Mota, Jorge Sequeiros, Claudia L. Oliveira, Sandra Martins, Ana F. Castro, José Leal Loureiro, Isabel Silveira, Joana R. Loureiro, and Instituto de Investigação e Inovação em Saúde

Subjects
Primates, Mutant, Biology, Chromosomes, Conserved sequence, Evolution, Molecular, 03 medical and health sciences, DNA Mutational Analysis, Genetics, medicine, Animals, Humans, Nerve Tissue Proteins / genetics, Allele, Alleles, Conserved Sequence, Phylogeny, Genetics (clinical), Repetitive Sequences, Nucleic Acid, 030304 developmental biology, 0303 health sciences, Base Sequence, Portugal, 030305 genetics & heredity, Haplotype, Ataxins / genetics, medicine.disease, 3. Good health, Mutagenesis, Insertional, Haplotypes, Case-Control Studies, Spinocerebellar ataxia, Adaptor Proteins, Signal Transducing / genetics, Human genome, Trinucleotide repeat expansion
Abstract

Dynamic mutations by microsatellite instability are the molecular basis of a growing number of neuromuscular and neurodegenerative diseases. Repetitive stretches in the human genome may drive pathogenicity, either by expansion above a given threshold, or by insertion of abnormal tracts in nonpathogenic polymorphic repetitive regions, as is the case in spinocerebellar ataxia type 37 (SCA37). We have recently established that this neurodegenerative disease is caused by an (ATTTC)n insertion within an (ATTTT)n in a noncoding region of DAB1. We now investigated the mutational mechanism that originated the (ATTTC)n insertion within an ancestral (ATTTT)n . Approximately 3% of nonpathogenic (ATTTT)n alleles are interspersed by AT-rich motifs, contrarily to mutant alleles that are composed of pure (ATTTT)n and (ATTTC)n stretches. Haplotype studies in unaffected chromosomes suggested that the primary mutational mechanism, leading to the (ATTTC)n insertion, was likely one or more T>C substitutions in an (ATTTT)n pure allele of approximately 200 repeats. Then, the (ATTTC)n expanded in size, originating a deleterious allele in DAB1 that leads to SCA37. This is likely the mutational mechanism in three similar (TTTCA)n insertions responsible for familial myoclonic epilepsy. Because (ATTTT)n tracts are frequent in the human genome, many loci could be at risk for this mutational process. We are grateful to the families and individuals who participated in this work. We thank Patricia Ribeiro for technical assistance. This study was financed by Fundo Europeu de Desenvolvimento Regional (FEDER), through the COMPETE 2020 Operational Pro- gram for Competitiveness and Internationalization (POCI) of Portugal 2020, and by the Fundacão para a Ciência e a Tecnologia (FCT) and Ministério da Ciência, Tecnologia e Ensino Superior (Portugal), in the framework of the project POCI-01-0145-FEDER-029255; (PTDC/MED-GEN/29255/2017) to I.S. J.R.L. and C.L.O. were sup- ported by scholarships from PEst-C/SAU/LA0002/2013. S.M. is funded by the project IF/00930/2013/ CP1184/CT0002 from FCT. This work was also funded by the Porto Neurosciences and Neurologic Disease Research Initiative at the Instituto de Investigação e Inovação em Saúde (Norte-01-0145-FEDER- 000008), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTU- GAL 2020 Partnership Agreement with FEDER.

Published
2019
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3. A repeat-primed PCR assay for pentanucleotide repeat alleles in spinocerebellar ataxia type 37

Author

Claudia L. Oliveira, Jorge Sequeiros, Isabel Silveira, Joana R. Loureiro, and Instituto de Investigação e Inovação em Saúde

Subjects
0301 basic medicine, Male, Pcr assay, Nerve Tissue Proteins, Biology, Spinocerebellar Ataxias / genetics, Polymerase Chain Reaction, law.invention, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, law, Polymerase Chain Reaction / methods, Genetics, medicine, Humans, Spinocerebellar Ataxias, Allele, Nerve Tissue Proteins / genetics, Genetics (clinical), Polymerase chain reaction, Alleles, Adaptor Proteins, Signal Transducing, Sanger sequencing, medicine.disease, Molecular biology, 3. Good health, Mutagenesis, Insertional, 030104 developmental biology, Spinocerebellar ataxia, symbols, Adaptor Proteins, Signal Transducing / genetics, Female, 030217 neurology & neurosurgery, Microsatellite Repeats
Abstract

Spinocerebellar ataxia 37 (SCA37) is caused by an (ATTTC)n insertion in a polymorphic ATTTT repeat in the non-coding region of DAB1. The non-pathogenic alleles have a configuration [(ATTTT)7-400], whereas pathogenic alleles have a complex structure of [(ATTTT)60-79(ATTTC)31-75(ATTTT)58-90]. Molecular diagnosis of SCA37 is laborious because about 7% of the pentanucleotide repeat alleles in DAB1 are larger than 30 units and, thus, fail to amplify with standard PCR conditions, resulting in apparently homoallelism or in complete lack of PCR amplification in several cases. The molecular test currently available requires long-range PCR and sequencing analysis for the detection and characterization of these large alleles. We developed a simple assay capable of rapidly detecting the presence or absence of large pentanucleotide repeat sizes. This assay is based on repeat-primed PCR followed by high-throughput capillary electrophoresis. Combining the standard PCR with RP-PCR allows completion of the diagnosis in more than 80% of individuals, minimizing the number of samples that require long-range PCR followed by Sanger sequencing analysis. This assay meets many of the requirements for pre-screening of large cohorts of affected individuals. This work was funded by Fundo Europeu de Desenvolvimento Regional-FEDER funds through the COMPETE 2020—Operational Programme for Competitiveness and Inter- nationalisation (POCI), Portugal 2020, and by funding from FCT— Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tec- nologia e Inovação, Portugal, in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145- FEDER-007274); by Grant PTDC/SAU-GMG/098305/2008, from FCT, to I.S. J.R.L. was supported by scholarships from Grant PTDC/ GMG-SAU/098305/2008, FCT, PEst- C/SAU/LA0002/2013 and EMBO (ASTF494-2015). C.L.O. was supported by a scholarship from PEst-C/SAU/LA0002/2013. This work was also funded by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER), Portugal, that supports the Norte-01-0145-FEDER-000008—Porto Neurosciences and Neurologic Disease Research Initiative at I3S.

Published
2018

4. Joint ancestry and association test indicate two distinct pathogenic pathways involved in classical dengue fever and dengue shock syndrome

Author

Bruno Cavadas, Luísa Pereira, Fanny Koeth, Etienne Simon-Loriere, Marisa Oliveira, Isabelle Casademont, Worachart Lert-itthiporn, Prida Malasit, Orlando Anunciação, Prapat Suriyaphol, Marina Penova, Richard Paul, Fumihiko Matsuda, Chiea Chuen Khor, Ampaiwan Chuansumrit, Kanchana Tangnararatchakit, Anavaj Sakuntabhai, Verónica Fernandes, Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, Siriraj Hospital, Mahidol University, Mahidol University [Bangkok], Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Pasteur Kyoto International Joint Research Unit for Integrative Vaccinomics [Kyoto, Japan], Institut Pasteur [Paris], Department of Pediatrics, Faculty of Medicine, Mahidol University [Bangkok]-Ramathibodi Hospital, National University of Singapore (NUS), French National Research Agency (ANR-10–INSB–04, Investments for the Future)., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Instituto de Investigação e Inovação em Saúde, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Universidade do Porto = University of Porto, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Universidade do Porto [Porto], Genome Institute of Singapore (GIS), Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, Centre National de Génotypage (CNG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
Male, Heredity, Basic Helix-Loop-Helix Transcription Factors / genetics, Thai People, Viral Nonstructural Proteins / genetics, MESH: Asia, Southeastern, Genome-wide association study, Genome, Viral / genetics, Dengue virus, MESH: Dengue Virus, Biochemistry, MESH: Genotype, 0302 clinical medicine, MESH: Basic Helix-Loop-Helix Transcription Factors, Odds Ratio, Ethnicities, Protein Phosphatase 2, MESH: Nerve Tissue Proteins, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, MESH: Asian Continental Ancestry Group, MESH: Protein Phosphatase 2, Genomics, Genomic Databases, Severe Dengue / ethnology, MESH: Infant, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, MESH: Repressor Proteins, MESH: Young Adult, Child, Preschool, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Metabolic Pathways, Carrier Proteins / genetics, MESH: Cell Nucleus, MESH: Gene Expression, Genotype, Bioinformatics, lcsh:RC955-962, Single-nucleotide polymorphism, MESH: Severe Dengue, MESH: Carrier Proteins, Serogroup, 03 medical and health sciences, Viral Proteins, Asian People, Sequence Motif Analysis, Cell Nucleus / virology, Genetic predisposition, Genetics, Xenobiotic Metabolism, Humans, MESH: Adolescent, MESH: Humans, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Haplotype, MESH: Child, Preschool, Public Health, Environmental and Occupational Health, Biology and Life Sciences, Computational Biology, Infant, MESH: Adult, lcsh:RA1-1270, Dengue Virus, medicine.disease, Tropical Diseases, MESH: Sulfotransferases, MESH: Cell Line, 030104 developmental biology, Severe Dengue / genetics, MESH: Genome-Wide Association Study, MESH: Viral Nonstructural Proteins, Population Groupings, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Carrier Proteins, MESH: Female, 030217 neurology & neurosurgery, 0301 basic medicine, Viral Diseases, Gene Expression, Repressor Proteins / genetics, MESH: Dengue, Viral Nonstructural Proteins, medicine.disease_cause, Dengue fever, Dengue Fever, Geographical Locations, Dengue, Cohort Studies, Database and Informatics Methods, Medicine and Health Sciences, Basic Helix-Loop-Helix Transcription Factors, Nerve Tissue Proteins / genetics, MESH: Cohort Studies, Asia, Southeastern, Type C Phospholipases / genetics, lcsh:Public aspects of medicine, MESH: Genetic Predisposition to Disease, Thailand, Phenotype, Europe, Genetic Mapping, Infectious Diseases, Dengue Virus / genetics, Asian Continental Ancestry Group / genetics, Female, Sulfotransferases, MESH: Genome, Viral, MESH: Type C Phospholipases, Sequence Analysis, Research Article, Neglected Tropical Diseases, Adult, lcsh:Arctic medicine. Tropical medicine, Adolescent, Dengue / virology, Dengue / genetics, Nerve Tissue Proteins, Genome, Viral, Biology, Genetic Predisposition, Research and Analysis Methods, Cell Line, Young Adult, medicine, Viral Proteins / genetics, Genetic Predisposition to Disease, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Severe Dengue, MESH: Thailand, Cell Nucleus, Protein Phosphatase 2 / genetics, MESH: Serogroup, Genome Analysis, MESH: Viral Proteins, MESH: Male, MESH: Odds Ratio, Repressor Proteins, Biological Databases, Metabolism, Haplotypes, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Type C Phospholipases, People and Places, Genetics of Disease, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Genome-Wide Association Study
Abstract

Ethnic diversity has been long considered as one of the factors explaining why the severe forms of dengue are more prevalent in Southeast Asia than anywhere else. Here we take advantage of the admixed profile of Southeast Asians to perform coupled association-admixture analyses in Thai cohorts. For dengue shock syndrome (DSS), the significant haplotypes are located in genes coding for phospholipase C members (PLCB4 added to previously reported PLCE1), related to inflammation of blood vessels. For dengue fever (DF), we found evidence of significant association with CHST10, AHRR, PPP2R5E and GRIP1 genes, which participate in the xenobiotic metabolism signaling pathway. We conducted functional analyses for PPP2R5E, revealing by immunofluorescence imaging that the coded protein co-localizes with both DENV1 and DENV2 NS5 proteins. Interestingly, only DENV2-NS5 migrated to the nucleus, and a deletion of the predicted top-linking motif in NS5 abolished the nuclear transfer. These observations support the existence of differences between serotypes in their cellular dynamics, which may contribute to differential infection outcome risk. The contribution of the identified genes to the genetic risk render Southeast and Northeast Asian populations more susceptible to both phenotypes, while African populations are best protected against DSS and intermediately protected against DF, and Europeans the best protected against DF but the most susceptible against DSS., Author summary Dengue fever is endemic in tropical and subtropical areas of East Asia and America, but globalization and climate changes are introducing vector and virus to the naïve regions of Europe and North America. In this work we conducted a statistically robust, coupled association-admixture test in two dengue cohorts from Thailand (classical dengue fever, DF, and dengue shock syndrome, DSS) and a published Vietnamese (DSS only) cohort. We identified new candidate genes associated with DF risk and confirmed known gene family association with DSS risk. In DF, phosphatase control is crucial, including through binding to viral proteins, as we showed for PPP2R5E protein co-localization with DENV1 and DENV2-NS5 proteins within liver cells and differential cellular localizations along time. In DSS, cytokine dynamics, inflammation and activation of vascular endothelium cells are dominant features. The particular genetic risk conferred by these genes indicates that Southeast and Northeast Asians are highly susceptible to both phenotypes, while Africans are best protected against DSS, and Europeans best protected against DF but the most susceptible against DSS.

Published
2018
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5. Analysis of (CAG) n Expansion in ATXN1, ATXN2 and ATXN3 in Chinese Patients With Multiple System Atrophy

Author

X. Zhou, C. Wang, D. Ding, Z. Chen, Y. Peng, H. Peng, X. Hou, P. Wang, W. Ye, T. Li, H. Yang, R. Qiu, K. Xia, J. Sequeiros, B. Tang, H. Jiang, and Instituto de Investigação e Inovação em Saúde

Subjects
0301 basic medicine, Male, Trinucleotide Repeats / genetics, Ataxin-2 / metabolismo, lcsh:Medicine, Disease, Repressor Proteins / genetics, Pathogenesis, 0302 clinical medicine, Trinucleotide Repeats, Gene Frequency, Ataxins / metabolismo, Ataxin-1 / genetics, Age of Onset, Nerve Tissue Proteins / genetics, Ataxin-3, lcsh:Science, Ataxin-1, Ataxin-2, Multidisciplinary, Ataxin-3 / metabolismo, Middle Aged, Phenotype, Ataxins, Spinocerebellar ataxia, Ataxin-1 / metabolism, Asian Continental Ancestry Group / genetics, Female, Adult, congenital, hereditary, and neonatal diseases and abnormalities, China, Repressor Proteins / metabolismo, Nerve Tissue Proteins, Biology, Spinocerebellar Ataxias / genetics, Article, Multiple System Atrophy / pathology, 03 medical and health sciences, Atrophy, Asian People, stomatognathic system, mental disorders, medicine, Spinocerebellar Ataxias, Humans, Gene, Aged, lcsh:R, Ataxin-2 / genetics, Ataxins / genetics, Multiple System Atrophy, medicine.disease, Multiple System Atrophy / metabolismo, nervous system diseases, Repressor Proteins, 030104 developmental biology, Increased risk, nervous system, Immunology, Ataxin-3 / genetics, lcsh:Q, Multiple System Atrophy / genetics, Trinucleotide Repeat Expansion, 030217 neurology & neurosurgery
Abstract

Multiple system atrophy (MSA) is a complex and multifactorial neurodegenerative disease, and its pathogenesis remains uncertain. Patients with MSA or spinocerebellar ataxia (SCA) show overlapping clinical phenotypes. Previous studies have reported that intermediate or long CAG expansions in SCA genes have been associated with other neurodegenerative disease. In this study, we screened for the number of CAG repeats in ATXN1, 2 and 3 in 200 patients with MSA and 314 healthy controls to evaluate possible associations between (CAG)n in these three polyQ-related genes and MSA. Our findings indicated that longer repeat lengths in ATXN2 were associated with increased risk for MSA in Chinese individuals. No relationship was observed between CAG repeat length in the three examined genes and age at onset (AO) of MSA. We are grateful to all of the subjects for their participation in our study. This study was supported by the National Natural Science Foundation of China (Nos 81471156, and 81771231 to Hong Jiang, Nos 81130021 and 81430023 to Beisha Tang), the National Key Research and Development Program of China (Nos 2016YFC0901504 and 2016YFC0905100 to Hong Jiang), the National Natural Science Foundation of China (No. 31401135 to Rong Qiu), and Clinical Research Funds of Xiangya Hospital (No. 2014L03 to Hong Jiang).

Published
2018

6. Absence of mutations in the LGI1 receptor ADAM22 gene in autosomal dominant lateral temporal epilepsy

Author

Elodie Chabrol, Samuel F. Berkovic, Stéphanie Baulac, Christel Depienne, Rui Mota, Fabienne Picard, Nanditat Bajaj, Luisa Mota-Vieira, Ingrid E. Scheffer, Jacinta M McMahon, Oriane Trouillard, Philippe Couarch, Michel Baulac, Isabelle Gourfinkel-An, Eric LeGuern, Baulac, Stéphanie, Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Epilepsy Research Centre, University of Melbourne, Department of Paediatrics [Melbourne], Melbourne Medical School [Melbourne], Faculty of Medicine, Dentistry and Health Sciences [Melbourne], University of Melbourne-University of Melbourne-Faculty of Medicine, Dentistry and Health Sciences [Melbourne], University of Melbourne-University of Melbourne, Department of Neurology, University Hospital and Medical School of Geneva, Epilepsy clinic, Siddharth Hospital Ltd., Hospital do Divino Espirito Santo, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, Candidate gene, DNA Mutational Analysis, ADAM22, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, Exon, 0302 clinical medicine, MESH: Genetic Screening, MESH: Child, MESH: Nerve Tissue Proteins, MESH: DNA Mutational Analysis, ADAM Proteins / genetics, Nerve Tissue Proteins / genetics, Child, Autosomal dominant lateral temporal epilepsy, Genetics, 0303 health sciences, Mutation, Major gene, Genetic Testing / methods, Neurology, MESH: Epilepsy, Temporal Lobe, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, LGI1, MESH: ADAM Proteins, Adult, MESH: Mutation, Adolescent, Nerve Tissue Proteins, Biology, 03 medical and health sciences, Epilepsy, Temporal Lobe / genetics, medicine, Humans, Genetic Testing, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Gene, 030304 developmental biology, MESH: Adolescent, Family Health, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Genetic heterogeneity, MESH: Adult, MESH: Male, ddc:616.8, DNA Mutational Analysis / methods, ADAM Proteins, Epilepsy, Temporal Lobe, Membrane protein, MESH: Family Health, Neurology (clinical), MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; Mutations in the LGI1 (leucine-rich, glioma inactivated 1) gene are found in less than a half of the families with autosomal dominant lateral temporal epilepsy (ADLTE), suggesting that ADLTE is a genetically heterogeneous disorder. Recently, it was shown that LGI1 is released by neurons and becomes part of a protein complex at the neuronal postsynaptic density where it is implicated in the regulation of glutamate-AMPA neurotransmission. Within this complex, LGI1 binds selectively to a neuronal specific membrane protein, ADAM22 (a disintegrin and metalloprotease). Since ADAM22 serves as a neuronal receptor for LGI1, the ADAM22 gene was considered a good candidate gene for ADLTE. We have therefore sequenced all coding exons and exon-intron flanking sites in the ADAM22 gene in the probands of 18 ADLTE families negative for LGI1 mutations. Although, we identified several synonymous and non-synonymous polymorphisms, we failed to identify disease-causing mutations, indicating that ADAM22 gene is probably not a major gene for this epilepsy syndrome.

Published
2007
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