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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

A non-functional galanin receptor-2 in a multiple sclerosis patient

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Autor(es):
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Garcia-Rosa, Sheila [1] ; Trivella, Daniela B. B. [2, 3, 4] ; Marques, Vanessa D. [5] ; Serafim, Rodolfo B. [6] ; Pereira, Jose G. C. [3] ; Lorenzi, Julio C. C. [7] ; Molfetta, Greice A. [7] ; Christo, Paulo P. [8] ; Olival, Guilherme S. [9] ; Marchitto, Vania B. T. [9] ; Brum, Doralina G. [10] ; Sabedot, Thais S. [7] ; Noushmehr, Houtan [7] ; Farias, Alessandro S. [11] ; Santos, Leonilda M. B. [11] ; Nogueira-Machado, Jose A. [8] ; Souza, Jorge E. S. [12] ; Romano, Camila M. [13] ; Conde, Rodrigo M. [5] ; Santos, Antonio C. [5] ; Guerreiro, Carlos T. [5] ; Schreuder, Willem H. [1] ; Gleber-Netto, Frederico O. [1] ; Amorim, Maria [1] ; Valieris, Renan [14] ; da Silva, Israel Tojal [14] ; Silva, Jr., Wilson A. [7, 15] ; Nunes, Diana N. [1] ; Oliveira, Paulo S. L. [3] ; Valente, Valeria [16] ; Arruda, Maria Augusta [17, 2, 4, 18, 19] ; Hill, Stephen J. [17, 2, 19] ; Barreira, Amilton A. [5] ; Dias-Neto, Emmanuel [1, 20]
Número total de Autores: 34
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[1] AC Camargo Canc Ctr, Lab Med Genom, Sao Paulo, SP - Brazil
[2] Univ Nottingham, Sch Life Sci, Cell Signalling Res Grp, Nottingham - England
[3] Ctr Res Energy & Mat CNPEM, Brazilian Biosci Natl Lab LNBio, Campinas, SP - Brazil
[4] Univ Nottingham, Queens Med Ctr, CAPES Univ Nottingham Programme Drug Discovery, Nottingham NG7 2UH - England
[5] Univ Sao Paulo, Med Sch Ribeirao Preto, Dept Neurosci, Clin Neuroimmunol Div, Ribeirao Preto, SP - Brazil
[6] Univ Sao Paulo, Med Sch Ribeirao Preto, Dept Cellular & Mol Biol, Ribeirao Preto, SP - Brazil
[7] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Genet, Ribeirao Preto, SP - Brazil
[8] Santa Casa Belo Horizonte, Curso Posgrad, Belo Horizonte, MG - Brazil
[9] Fac Ciencias Med Santa Casa Sao Paulo, Neurosci Res Grp, Sao Paulo, SP - Brazil
[10] Univ State Sao Paulo UNESP, Sch Med Botucatu, Dept Neurol Psychol & Psychiat, Botucatu, SP - Brazil
[11] Univ Campinas UNICAMP, Inst Biol, Neuroimmunol Unit, Campinas, SP - Brazil
[12] Univ Fed Rio Grande do Norte, Inst Metropole Digital, Natal, RN - Brazil
[13] Univ Sao Paulo, Hosp Clin HCFMUSP, Fac Med, Lab Virol LIM52, Sao Paulo, SP - Brazil
[14] AC Camargo Canc Ctr, Lab Bioinformat & Computat Biol, Sao Paulo - Brazil
[15] Univ Sao Paulo, Ctr Med Genom HCFMRP, Ribeirao Preto - Brazil
[16] Sao Paulo State Univ UNESP, Sch Pharmaceut Sci, Araraquara, SP - Brazil
[17] Univ Nottingham, Nottingham - England
[18] Fiocruz MS, Farmanguinhos, Rio De Janeiro - Brazil
[19] Univ Birmingham, Ctr Membrane Prot & Receptors COMPARE, Birmingham, W Midlands - England
[20] Univ Sao Paulo, Sch Med, Inst Psychiat, Lab Neurosci LIM27, Sao Paulo, SP - Brazil
Número total de Afiliações: 20
Tipo de documento: Artigo Científico
Fonte: PHARMACOGENOMICS JOURNAL; v. 19, n. 1, p. 72-82, FEB 2019.
Citações Web of Science: 1
Resumo

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. (AU)

Processo FAPESP: 15/07925-5 - Softwares de código aberto contendo ferramentas estatísticas para análise e integração de conjuntos de dados epigenômicos produzidos em alta escala, a fim de decifrar e entender redes reguladoras de câncer
Beneficiário:Houtan Noushmehr
Linha de fomento: Auxílio à Pesquisa - Apoio a Jovens Pesquisadores
Processo FAPESP: 13/24293-7 - Investigação de mutações de novo como possível base biológica da esclerose múltipla
Beneficiário:Sheila Garcia
Linha de fomento: Bolsas no Brasil - Mestrado
Processo FAPESP: 16/06488-3 - Análise integrativa do epigenoma de gliomas com fenótipo metilador de ilhas CpG (G-CIMP) alto e baixo: caracterização e desenvolvimento
Beneficiário:Thaís Sarraf Sabedot
Linha de fomento: Bolsas no Brasil - Doutorado Direto