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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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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]
Total Authors: 34
Affiliation:
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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
Total Affiliations: 20
Document type: Journal article
Source: PHARMACOGENOMICS JOURNAL; v. 19, n. 1, p. 72-82, FEB 2019.
Web of Science Citations: 2
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. (AU)

FAPESP's process: 15/07925-5 - Open source software statistical tools to aid in analyzing and integrating large cancer epigenomic datasets in order to decipher and understand regulatory networks
Grantee:Houtan Noushmehr
Support type: Research Grants - Young Investigators Grants
FAPESP's process: 13/24293-7 - Investigation of de novo mutations as a possible basis biological of multiple sclerosis
Grantee:Sheila Garcia
Support type: Scholarships in Brazil - Master
FAPESP's process: 16/06488-3 - Integrative epigenomic analysis of high and low Glioma-CpG island Methylator Phenotype (G-CIMP): characterization and methods development
Grantee:Thaís Sarraf Sabedot
Support type: Scholarships in Brazil - Doctorate (Direct)