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dc.contributor.authorGarcia-Rosa, Sheila
dc.contributor.authorTrivella, Daniela Bb
dc.contributor.authorMarques, Vanessa D
dc.contributor.authorSerafim, Rodolfo B
dc.contributor.authorPereira, José Gc
dc.contributor.authorLorenzi, Julio Cc
dc.contributor.authorMolfetta, Greice A
dc.contributor.authorChristo, Paulo P
dc.contributor.authorOlival, Guilherme S
dc.contributor.authorMarchitto, Vania Bt
dc.contributor.authorBrum, Doralina G [UNESP]
dc.contributor.authorSabedot, Thais S
dc.contributor.authorNoushmehr, Houtan
dc.contributor.authorFarias, Alessandro S
dc.contributor.authorSantos, Leonilda Mb
dc.contributor.authorNogueira-Machado, José A
dc.contributor.authorSouza, Jorge Es
dc.contributor.authorRomano, Camila M
dc.contributor.authorConde, Rodrigo M
dc.contributor.authorSantos, Antonio C
dc.contributor.authorGuerreiro, Carlos T
dc.contributor.authorSchreuder, Willem H
dc.contributor.authorGleber-Netto, Frederico O
dc.contributor.authorAmorim, Maria
dc.contributor.authorValieris, Renan
dc.contributor.authorSilva, Israel Tojal da
dc.contributor.authorSilva, Wilson A
dc.contributor.authorNunes, Diana N
dc.contributor.authorOliveira, Paulo Sl
dc.contributor.authorValente, Valeria [UNESP]
dc.contributor.authorArruda, Maria Augusta
dc.contributor.authorHill, Stephen J
dc.contributor.authorBarreira, Amilton A
dc.contributor.authorDias-Neto, Emmanuel
dc.identifier.citationPharmacogenomics Journal.
dc.description.abstractMultiple 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.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.relation.ispartofPharmacogenomics Journal
dc.titleA non-functional galanin receptor-2 in a multiple sclerosis patienten
dc.contributor.institutionAC Camargo Cancer Center
dc.contributor.institutionCenter for Research in Energy and Material (CNPEM)
dc.contributor.institutionQueen’s Medical Centre University of Nottingham
dc.contributor.institutionUniversity of Nottingham
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionSanta Casa de Belo Horizonte
dc.contributor.institutionFaculdade de Ciências Médicas da Santa Casa de São Paulo
dc.contributor.institutionUniversidade Estadual Paulista (UNESP)
dc.contributor.institutionUniversidade Estadual de Campinas (UNICAMP)
dc.contributor.institutionFederal University of Rio Grande do Norte
dc.contributor.institutionUniversity of Birmingham and University of Nottingham
dc.description.affiliationLab. of Medical Genomics AC Camargo Cancer Center
dc.description.affiliationBrazilian Biosciences National Laboratory (LNBio) Center for Research in Energy and Material (CNPEM)
dc.description.affiliationCAPES-University of Nottingham Programme in Drug Discovery Queen’s Medical Centre University of Nottingham
dc.description.affiliationCell Signalling Research Group School of Life Sciences University of Nottingham
dc.description.affiliationDepartment of Neurosciences Clinical Neuroimmunology Division Medical School of Ribeirão Preto University of São Paulo (USP)
dc.description.affiliationDepartment of Cellular and Molecular Biology Medical School of Ribeirão Preto University of São Paulo (USP)
dc.description.affiliationDepartment of Genetics Ribeirão Preto Medical School University of São Paulo (USP)
dc.description.affiliationCurso de Pós-Graduação Santa Casa de Belo Horizonte
dc.description.affiliationNeurosciences Research Group Faculdade de Ciências Médicas da Santa Casa de São Paulo
dc.description.affiliationDepartment of Neurology Psychology and Psychiatry School of Medicine of Botucatu University of State of São Paulo (UNESP)
dc.description.affiliationNeuroimmunology Unit Institute of Biology University of Campinas (UNICAMP)
dc.description.affiliationInstituto Metrópole Digital Federal University of Rio Grande do Norte
dc.description.affiliationLab. Virology (LIM52) Hospital das Clinicas HCFMUSP Faculdade de Medicina Universidade de Sao Paulo
dc.description.affiliationLaboratory of Bioinformatics and Computational Biology AC Camargo Cancer Center
dc.description.affiliationCenter for Medical Genomics at HCFMRP Universidade de Sao Paulo (USP)
dc.description.affiliationSchool of Pharmaceutical Sciences São Paulo State University (UNESP)
dc.description.affiliationFarmanguinhos Fiocruz
dc.description.affiliationCentre of Membrane Proteins and Receptors (COMPARE) University of Birmingham and University of Nottingham
dc.description.affiliationLab. of Neurosciences (LIM27) Institute of Psychiatry School of Medicine University of São Paulo USP
dc.description.affiliationUnespDepartment of Neurology Psychology and Psychiatry School of Medicine of Botucatu University of State of São Paulo (UNESP)
dc.description.affiliationUnespSchool of Pharmaceutical Sciences São Paulo State University (UNESP)
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