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.

Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease

“…The genes harboring rare disease-causing variants for familial MS, herein or previously described [9–12], play critical roles in cellular cation homeostasis, and the regulation of transcription and activation of inflammatory mediators; suggesting a disruption of the innate immune system as the common underlying biological mechanism for the initiation of MS symptoms (Fig 3). Variants in PLAU , MASP1 , and C2 , as well as risk alleles in PLG and PLAU [6, 20], suggests a disruption in the fibrinolysis and complement cascade in response to microbial threads or cellular debris as a trigger for MS.…”

“…In these families, rare variants co-segregating with MS are likely to account for the highest attributable risk towards the disease; however, additional genetic and environmental factors are expected to play a significant role in the presentation of clinical symptoms, level of disability, disease progression, penetrance and onset age [8, 9]. The application of whole-exome sequencing (WES) in MS families has already nominated pathogenic mutations in NR1H3 , P2RX4/P2RX7 , NLRP1 and GALR2 [9–12]. Although only one of these discoveries has been replicated [13], mutations responsible for Mendelian forms of MS highlight the molecular mechanisms underlying the cause of disease, and provide the means for the generation of new cellular and animal models of MS based on human genetic etiology [9].…”

Intranasal Delivery of a Methyllanthionine-Stabilized Galanin Receptor-2-Selective Agonist Reduces Acute Food Intake

“…GAL 2 R has, for instance, been reported to be neuroprotective in experimental autoimmune encephalomyelitis and a cuprizone model mimicking aspects of multiple sclerosis [70,71]. A non-functional GAL 2 R in a multiple sclerosis patient has been reported [72], indicating a potential therapeutic role for stimulation of GAL 2 R in this disease. The current study raises the possibility of an antiobesity effect of M89b that could be confirmed via chronic or repeated administration in future studies.…”

Predicting Multiple Sclerosis: Challenges and Opportunities

“…Evidence from the IMSGC case-control exome chip study analyzing the role of rare coding variants suggests that a further ∼10% of MS heritability may be explained by rare (Minor Allele Frequency < 0.05) variants (4). Neither these substantial gene discovery efforts nor smaller pedigree designs have discovered any reproducible single-gene causes of MS (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Although rare monogenic forms of MS not captured in these studies cannot be excluded, these data argue for MS being a prototypical complex and polygenic disease.…”