A non-functional galanin receptor-2 in a multiple sclerosis patient
dc.contributor.author | Garcia-Rosa, Sheila | |
dc.contributor.author | Trivella, Daniela Bb | |
dc.contributor.author | Marques, Vanessa D | |
dc.contributor.author | Serafim, Rodolfo B | |
dc.contributor.author | Pereira, José Gc | |
dc.contributor.author | Lorenzi, Julio Cc | |
dc.contributor.author | Molfetta, Greice A | |
dc.contributor.author | Christo, Paulo P | |
dc.contributor.author | Olival, Guilherme S | |
dc.contributor.author | Marchitto, Vania Bt | |
dc.contributor.author | Brum, Doralina G [UNESP] | |
dc.contributor.author | Sabedot, Thais S | |
dc.contributor.author | Noushmehr, Houtan | |
dc.contributor.author | Farias, Alessandro S | |
dc.contributor.author | Santos, Leonilda Mb | |
dc.contributor.author | Nogueira-Machado, José A | |
dc.contributor.author | Souza, Jorge Es | |
dc.contributor.author | Romano, Camila M | |
dc.contributor.author | Conde, Rodrigo M | |
dc.contributor.author | Santos, Antonio C | |
dc.contributor.author | Guerreiro, Carlos T | |
dc.contributor.author | Schreuder, Willem H | |
dc.contributor.author | Gleber-Netto, Frederico O | |
dc.contributor.author | Amorim, Maria | |
dc.contributor.author | Valieris, Renan | |
dc.contributor.author | Silva, Israel Tojal da | |
dc.contributor.author | Silva, Wilson A | |
dc.contributor.author | Nunes, Diana N | |
dc.contributor.author | Oliveira, Paulo Sl | |
dc.contributor.author | Valente, Valeria [UNESP] | |
dc.contributor.author | Arruda, Maria Augusta | |
dc.contributor.author | Hill, Stephen J | |
dc.contributor.author | Barreira, Amilton A | |
dc.contributor.author | Dias-Neto, Emmanuel | |
dc.contributor.institution | AC Camargo Cancer Center | |
dc.contributor.institution | Center for Research in Energy and Material (CNPEM) | |
dc.contributor.institution | Queen’s Medical Centre University of Nottingham | |
dc.contributor.institution | University of Nottingham | |
dc.contributor.institution | Universidade de São Paulo (USP) | |
dc.contributor.institution | Santa Casa de Belo Horizonte | |
dc.contributor.institution | Faculdade de Ciências Médicas da Santa Casa de São Paulo | |
dc.contributor.institution | Universidade Estadual Paulista (Unesp) | |
dc.contributor.institution | Universidade Estadual de Campinas (UNICAMP) | |
dc.contributor.institution | Federal University of Rio Grande do Norte | |
dc.contributor.institution | Fiocruz | |
dc.contributor.institution | University of Birmingham and University of Nottingham | |
dc.date.accessioned | 2018-12-11T17:22:26Z | |
dc.date.available | 2018-12-11T17:22:26Z | |
dc.date.issued | 2018-01-01 | |
dc.description.abstract | Multiple Sclerosis (MS) is an inflammatory neurodegenerative disease that affects approximately 2.5 million people globally. Even though the etiology of MS remains unknown, it is accepted that it involves a combination of genetic alterations and environmental factors. Here, after performing whole exome sequencing, we found a MS patient harboring a rare and homozygous single nucleotide variant (SNV; rs61745847) of the G-protein coupled receptor (GPCR) galanin-receptor 2 (GALR2) that alters an important amino acid in the TM6 molecular toggle switch region (W249L). Nuclear magnetic resonance imaging showed that the hypothalamus (an area rich in GALR2) of this patient exhibited an important volumetric reduction leading to an enlarged third ventricle. Ex vivo experiments with patient-derived blood cells (AKT phosphorylation), as well as studies in recombinant cell lines expressing the human GALR2 (calcium mobilization and NFAT mediated gene transcription), showed that galanin (GAL) was unable to stimulate cell signaling in cells expressing the variant GALR2 allele. Live cell confocal microscopy showed that the GALR2 mutant receptor was primarily localized to intracellular endosomes. We conclude that the W249L SNV is likely to abrogate GAL-mediated signaling through GALR2 due to the spontaneous internalization of this receptor in this patient. Although this homozygous SNV was rare in our MS cohort (1:262 cases), our findings raise the potential importance of impaired neuroregenerative pathways in the pathogenesis of MS, warrant future studies into the relevance of the GAL/GALR2 axis in MS and further suggest the activation of GALR2 as a potential therapeutic route for this disease. | en |
dc.description.affiliation | Lab. of Medical Genomics AC Camargo Cancer Center | |
dc.description.affiliation | Brazilian Biosciences National Laboratory (LNBio) Center for Research in Energy and Material (CNPEM) | |
dc.description.affiliation | CAPES-University of Nottingham Programme in Drug Discovery Queen’s Medical Centre University of Nottingham | |
dc.description.affiliation | Cell Signalling Research Group School of Life Sciences University of Nottingham | |
dc.description.affiliation | Department of Neurosciences Clinical Neuroimmunology Division Medical School of Ribeirão Preto University of São Paulo (USP) | |
dc.description.affiliation | Department of Cellular and Molecular Biology Medical School of Ribeirão Preto University of São Paulo (USP) | |
dc.description.affiliation | Department of Genetics Ribeirão Preto Medical School University of São Paulo (USP) | |
dc.description.affiliation | Curso de Pós-Graduação Santa Casa de Belo Horizonte | |
dc.description.affiliation | Neurosciences Research Group Faculdade de Ciências Médicas da Santa Casa de São Paulo | |
dc.description.affiliation | Department of Neurology Psychology and Psychiatry School of Medicine of Botucatu University of State of São Paulo (UNESP) | |
dc.description.affiliation | Neuroimmunology Unit Institute of Biology University of Campinas (UNICAMP) | |
dc.description.affiliation | Instituto Metrópole Digital Federal University of Rio Grande do Norte | |
dc.description.affiliation | Lab. Virology (LIM52) Hospital das Clinicas HCFMUSP Faculdade de Medicina Universidade de Sao Paulo | |
dc.description.affiliation | Laboratory of Bioinformatics and Computational Biology AC Camargo Cancer Center | |
dc.description.affiliation | Center for Medical Genomics at HCFMRP Universidade de Sao Paulo (USP) | |
dc.description.affiliation | School of Pharmaceutical Sciences São Paulo State University (UNESP) | |
dc.description.affiliation | Farmanguinhos Fiocruz | |
dc.description.affiliation | Centre of Membrane Proteins and Receptors (COMPARE) University of Birmingham and University of Nottingham | |
dc.description.affiliation | Lab. of Neurosciences (LIM27) Institute of Psychiatry School of Medicine University of São Paulo USP | |
dc.description.affiliationUnesp | Department of Neurology Psychology and Psychiatry School of Medicine of Botucatu University of State of São Paulo (UNESP) | |
dc.description.affiliationUnesp | School of Pharmaceutical Sciences São Paulo State University (UNESP) | |
dc.description.sponsorship | Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) | |
dc.identifier | http://dx.doi.org/10.1038/s41397-018-0032-6 | |
dc.identifier.citation | Pharmacogenomics Journal. | |
dc.identifier.doi | 10.1038/s41397-018-0032-6 | |
dc.identifier.issn | 1473-1150 | |
dc.identifier.issn | 1470-269X | |
dc.identifier.scopus | 2-s2.0-85052608412 | |
dc.identifier.uri | http://hdl.handle.net/11449/176774 | |
dc.language.iso | eng | |
dc.relation.ispartof | Pharmacogenomics Journal | |
dc.relation.ispartofsjr | 1,320 | |
dc.rights.accessRights | Acesso restrito | |
dc.source | Scopus | |
dc.title | A non-functional galanin receptor-2 in a multiple sclerosis patient | en |
dc.type | Artigo | |
unesp.author.orcid | 0000-0002-7505-2345[2] | |
unesp.author.orcid | 0000-0001-7847-9902[23] | |
unesp.author.orcid | 0000-0002-1287-8019[29] | |
unesp.author.orcid | 0000-0002-0828-9430[31] |