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

Sheila Garcia-Rosa, Daniela Bb Trivella, Vanessa D. Marques, Rodolfo B. Serafim, José Gc Pereira, Julio Cc Lorenzi, Greice A. Molfetta, Paulo P. Christo, Guilherme S. Olival, Vania Bt Marchitto, Doralina G. Brum, Thais S. Sabedot, Houtan Noushmehr, Alessandro S. Farias, Leonilda Mb Santos, José A. Nogueira-Machado, Jorge Es Souza, Camila M. Romano, Rodrigo M. Conde, Antonio C. Santos & 14 others Carlos T. Guerreiro, Willem H. Schreuder, Frederico Omar Gleber Netto, Maria Amorim, Renan Valieris, Israel Tojal da Silva, Wilson A. Silva, Diana N. Nunes, Paulo Sl Oliveira, Valeria Valente, Maria Augusta Arruda, Stephen J. Hill, Amilton A. Barreira, Emmanuel Dias-Neto

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)72-82
Number of pages11
JournalPharmacogenomics Journal
Volume19
Issue number1
DOIs
StatePublished - Feb 1 2019

Fingerprint

Receptor, Galanin, Type 2
Multiple Sclerosis
Galanin
Exome
Third Ventricle
Endosomes
G-Protein-Coupled Receptors
Confocal Microscopy
Neurodegenerative Diseases
Hypothalamus
Blood Cells
Magnetic Resonance Spectroscopy
Nucleotides
Alleles
Phosphorylation
Magnetic Resonance Imaging

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Pharmacology

Cite this

Garcia-Rosa, S., Trivella, D. B., Marques, V. D., Serafim, R. B., Pereira, J. G., Lorenzi, J. C., ... Dias-Neto, E. (2019). A non-functional galanin receptor-2 in a multiple sclerosis patient. Pharmacogenomics Journal, 19(1), 72-82. https://doi.org/10.1038/s41397-018-0032-6

A non-functional galanin receptor-2 in a multiple sclerosis patient. / Garcia-Rosa, Sheila; Trivella, Daniela Bb; Marques, Vanessa D.; Serafim, Rodolfo B.; Pereira, José Gc; Lorenzi, Julio Cc; Molfetta, Greice A.; Christo, Paulo P.; Olival, Guilherme S.; Marchitto, Vania Bt; Brum, Doralina G.; Sabedot, Thais S.; Noushmehr, Houtan; Farias, Alessandro S.; Santos, Leonilda Mb; Nogueira-Machado, José A.; Souza, Jorge Es; Romano, Camila M.; Conde, Rodrigo M.; Santos, Antonio C.; Guerreiro, Carlos T.; Schreuder, Willem H.; Netto, Frederico Omar Gleber; Amorim, Maria; Valieris, Renan; Silva, Israel Tojal da; Silva, Wilson A.; Nunes, Diana N.; Oliveira, Paulo Sl; Valente, Valeria; Arruda, Maria Augusta; Hill, Stephen J.; Barreira, Amilton A.; Dias-Neto, Emmanuel.

In: Pharmacogenomics Journal, Vol. 19, No. 1, 01.02.2019, p. 72-82.

Research output: Contribution to journalArticle

Garcia-Rosa, S, Trivella, DB, Marques, VD, Serafim, RB, Pereira, JG, Lorenzi, JC, Molfetta, GA, Christo, PP, Olival, GS, Marchitto, VB, Brum, DG, Sabedot, TS, Noushmehr, H, Farias, AS, Santos, LM, Nogueira-Machado, JA, Souza, JE, Romano, CM, Conde, RM, Santos, AC, Guerreiro, CT, Schreuder, WH, Netto, FOG, Amorim, M, Valieris, R, Silva, ITD, Silva, WA, Nunes, DN, Oliveira, PS, Valente, V, Arruda, MA, Hill, SJ, Barreira, AA & Dias-Neto, E 2019, 'A non-functional galanin receptor-2 in a multiple sclerosis patient' Pharmacogenomics Journal, vol. 19, no. 1, pp. 72-82. https://doi.org/10.1038/s41397-018-0032-6
Garcia-Rosa S, Trivella DB, Marques VD, Serafim RB, Pereira JG, Lorenzi JC et al. A non-functional galanin receptor-2 in a multiple sclerosis patient. Pharmacogenomics Journal. 2019 Feb 1;19(1):72-82. https://doi.org/10.1038/s41397-018-0032-6
Garcia-Rosa, Sheila ; Trivella, Daniela Bb ; Marques, Vanessa D. ; Serafim, Rodolfo B. ; Pereira, José Gc ; Lorenzi, Julio Cc ; Molfetta, Greice A. ; Christo, Paulo P. ; Olival, Guilherme S. ; Marchitto, Vania Bt ; Brum, Doralina G. ; Sabedot, Thais S. ; Noushmehr, Houtan ; Farias, Alessandro S. ; Santos, Leonilda Mb ; Nogueira-Machado, José A. ; Souza, Jorge Es ; Romano, Camila M. ; Conde, Rodrigo M. ; Santos, Antonio C. ; Guerreiro, Carlos T. ; Schreuder, Willem H. ; Netto, Frederico Omar Gleber ; Amorim, Maria ; Valieris, Renan ; Silva, Israel Tojal da ; Silva, Wilson A. ; Nunes, Diana N. ; Oliveira, Paulo Sl ; Valente, Valeria ; Arruda, Maria Augusta ; Hill, Stephen J. ; Barreira, Amilton A. ; Dias-Neto, Emmanuel. / A non-functional galanin receptor-2 in a multiple sclerosis patient. In: Pharmacogenomics Journal. 2019 ; Vol. 19, No. 1. pp. 72-82.
@article{d736867738c94a62bd3be7b43c0cc0ef,
title = "A non-functional galanin receptor-2 in a multiple sclerosis patient",
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.",
author = "Sheila Garcia-Rosa and Trivella, {Daniela Bb} and Marques, {Vanessa D.} and Serafim, {Rodolfo B.} and Pereira, {Jos{\'e} Gc} and Lorenzi, {Julio Cc} and Molfetta, {Greice A.} and Christo, {Paulo P.} and Olival, {Guilherme S.} and Marchitto, {Vania Bt} and Brum, {Doralina G.} and Sabedot, {Thais S.} and Houtan Noushmehr and Farias, {Alessandro S.} and Santos, {Leonilda Mb} and Nogueira-Machado, {Jos{\'e} A.} and Souza, {Jorge Es} and Romano, {Camila M.} and Conde, {Rodrigo M.} and Santos, {Antonio C.} and Guerreiro, {Carlos T.} and Schreuder, {Willem H.} and Netto, {Frederico Omar Gleber} and Maria Amorim and Renan Valieris and Silva, {Israel Tojal da} and Silva, {Wilson A.} and Nunes, {Diana N.} and Oliveira, {Paulo Sl} and Valeria Valente and Arruda, {Maria Augusta} and Hill, {Stephen J.} and Barreira, {Amilton A.} and Emmanuel Dias-Neto",
year = "2019",
month = "2",
day = "1",
doi = "10.1038/s41397-018-0032-6",
language = "English (US)",
volume = "19",
pages = "72--82",
journal = "Pharmacogenomics Journal",
issn = "1470-269X",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - A non-functional galanin receptor-2 in a multiple sclerosis patient

AU - Garcia-Rosa, Sheila

AU - Trivella, Daniela Bb

AU - Marques, Vanessa D.

AU - Serafim, Rodolfo B.

AU - Pereira, José Gc

AU - Lorenzi, Julio Cc

AU - Molfetta, Greice A.

AU - Christo, Paulo P.

AU - Olival, Guilherme S.

AU - Marchitto, Vania Bt

AU - Brum, Doralina G.

AU - Sabedot, Thais S.

AU - Noushmehr, Houtan

AU - Farias, Alessandro S.

AU - Santos, Leonilda Mb

AU - Nogueira-Machado, José A.

AU - Souza, Jorge Es

AU - Romano, Camila M.

AU - Conde, Rodrigo M.

AU - Santos, Antonio C.

AU - Guerreiro, Carlos T.

AU - Schreuder, Willem H.

AU - Netto, Frederico Omar Gleber

AU - Amorim, Maria

AU - Valieris, Renan

AU - Silva, Israel Tojal da

AU - Silva, Wilson A.

AU - Nunes, Diana N.

AU - Oliveira, Paulo Sl

AU - Valente, Valeria

AU - Arruda, Maria Augusta

AU - Hill, Stephen J.

AU - Barreira, Amilton A.

AU - Dias-Neto, Emmanuel

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85052608412&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052608412&partnerID=8YFLogxK

U2 - 10.1038/s41397-018-0032-6

DO - 10.1038/s41397-018-0032-6

M3 - Article

VL - 19

SP - 72

EP - 82

JO - Pharmacogenomics Journal

JF - Pharmacogenomics Journal

SN - 1470-269X

IS - 1

ER -