Abstract
Genetic and functional analyses of the inflammasome suggest a role for this multiprotein complex in the biological mechanisms leading to the onset and progression of multiple sclerosis (MS). Nucleotide-binding, leucine-rich repeat (NLR) receptors trigger the activation and assembly of specific inflammasomes in response to danger signals. Mining exome sequencing data from 326 MS patients identified 17 rare missense or nonsense variants in NLR family pyrin domain containing 1 (NLRP1), NLRP3, NLRP6, NLRP7 and NLR family CARD domain containing 4 (NLRC4). Genotyping these variants in 2503 MS cases and 1076 healthy controls did not result in statistically significant differences between groups, and segregation analysis within MS families was largely unsupportive of co-segregation of these variants with disease. However, the identification of MS patients harboring rare homozygote variants in NLRP1 (p.Ile601Phe and p.Ser1387Ile), a variant in NLRP3 (p.Leu832Ile) resulting in the substitution of a critical amino acid for the formation of its leucine-rich repeat domain, and several MS patients with NLRC4 variants (p.Arg310Ter and p.Glu600Ter) causing protein truncations suggest that rare protein-altering variants in inflammasome-activating NLR receptors may contribute to MS risk.
This is a preview of subscription content, log in via an institution to check access.
References
Broderick L, De Nardo D, Franklin BS, Hoffman HM, Latz E (2015) The inflammasomes and autoinflammatory syndromes. Annu Rev Pathol 10:395–424. https://doi.org/10.1146/annurev-pathol-012414-040431
Davydov EV, Goode DL, Sirota M, Cooper GM, Sidow A, Batzoglou S (2010) Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput Biol 6:e1001025. https://doi.org/10.1371/journal.pcbi.1001025
Gharagozloo M et al (2019) NLRX1 inhibits the early stages of CNS inflammation and prevents the onset of spontaneous autoimmunity. PLoS Biol 17:e3000451. https://doi.org/10.1371/journal.pbio.3000451
Gharagozloo M et al (2015) The nod-like receptor, Nlrp12, plays an anti-inflammatory role in experimental autoimmune encephalomyelitis. J Neuroinflammation 12:198. https://doi.org/10.1186/s12974-015-0414-5
Gil-Varea E, Urcelay E, Vilariño-Güell C, Costa C, Midaglia L, Matesanz F, Rodríguez-Antigüedad A, Oksenberg J, Espino-Paisan L, Dessa Sadovnick A, Saiz A, Villar LM, García-Merino JA, Ramió-Torrentà L, Triviño JC, Quintana E, Robles R, Sánchez-López A, Arroyo R, Alvarez-Cermeño JC, Vidal-Jordana A, Malhotra S, Fissolo N, Montalban X, Comabella M (2018) Exome sequencing study in patients with multiple sclerosis reveals variants associated with disease course. J Neuroinflammation 15:265. https://doi.org/10.1186/s12974-018-1307-1
Gris D et al (2010) NLRP3 plays a critical role in the development of experimental autoimmune encephalomyelitis by mediating Th1 and Th17 responses. J Immunol 185:974–981. https://doi.org/10.4049/jimmunol.0904145
Kawana N, Yamamoto Y, Ishida T, Saito Y, Konno H, Arima K, Satoh J (2013) Reactive astrocytes and perivascular macrophages express NLRP3 inflammasome in active demyelinating lesions of multiple sclerosis and necrotic lesions of neuromyelitis optica and cerebral infarction clinical and experimental. Neuroimmunology 4:296–304. https://doi.org/10.1111/cen3.12068
Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J (2014) A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46:310–315. https://doi.org/10.1038/ng.2892
Lek M et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291. https://doi.org/10.1038/nature19057
Malhotra S et al. (2020) NLRP3 inflammasome as prognostic factor and therapeutic target in primary progressive multiple sclerosis patients. Brain : a journal of neurology 143:1414–1430. https://doi.org/10.1093/brain/awaa084
Maver A et al (2017) Identification of rare genetic variation of NLRP1 gene in familial multiple sclerosis. Sci Rep 7:3715. https://doi.org/10.1038/s41598-017-03536-9
Olcum M, Tastan B, Kiser C, Genc S, Genc K (2020) Microglial NLRP3 inflammasome activation in multiple sclerosis. Adv protein Chem Struct Biol 119:247–308. https://doi.org/10.1016/bs.apcsb.2019.08.007
Peelen E, Damoiseaux J, Muris AH, Knippenberg S, Smolders J, Hupperts R, Thewissen M (2015) Increased inflammasome related gene expression profile in PBMC may facilitate T helper 17 cell induction in multiple sclerosis. Mol Immunol 63:521–529. https://doi.org/10.1016/j.molimm.2014.10.008
Sadovnick AD et al (2017a) Purinergic receptors P2RX4 and P2RX7 in familial multiple sclerosis hum. Mutat 38:736–744. https://doi.org/10.1002/humu.23218
Sadovnick AD et al (2017b) Genetic modifiers of multiple sclerosis progression, severity and onset. Clin Immunol 180:100–105. https://doi.org/10.1016/j.clim.2017.05.009
Soares JL, Oliveira EM, Pontillo A (2019) Variants in NLRP3 and NLRC4 inflammasome associate with susceptibility and severity of multiple sclerosis. Multiple Sclerosis and Related Disorders 29:26–34. https://doi.org/10.1016/j.msard.2019.01.023
Traboulsee AL, Bernales CQ, Ross JP, Lee JD, Sadovnick AD, Vilarino-Guell C (2014) Genetic variants in IL2RA and IL7R affect multiple sclerosis disease risk and progression. Neurogenetics 15:165–169. https://doi.org/10.1007/s10048-014-0403-3
Traboulsee AL, Sadovnick AD, Encarnacion M, Bernales CQ, Yee IM, Criscuoli MG, Vilarino-Guell C (2017) Common genetic etiology between “multiple sclerosis-like” single-gene disorders and familial multiple sclerosis. Hum Genet 136:705–714. https://doi.org/10.1007/s00439-017-1784-9
Vilarino-Guell C et al (2019) Exome sequencing in multiple sclerosis families identifies 12 candidate genes and nominates biological pathways for the genesis of disease. PLoS Genet 15:e1008180. https://doi.org/10.1371/journal.pgen.1008180
Wang Z et al (2016) Nuclear receptor NR1H3 in familial multiple sclerosis. Neuron 90:948–954. https://doi.org/10.1016/j.neuron.2016.04.039
Acknowledgments
We are grateful to all individuals who generously participated in this study.
Funding
This research was funded by the Michael Smith Foundation for Health Research (16827), Canadian Institutes of Health Research (MOP-137051), Vancouver Coastal Health Research Institute, the Milan & Maureen Ilich Foundation (11–32,095,000), and the Vancouver Foundation (ADV14–1597).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Ethical approval
All participants were collected through the longitudinal Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis with informed consent and approval from the ethical review board at the University of British Columbia.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
(PDF 3.09 mb)
Rights and permissions
About this article
Cite this article
Popplewell, L.F., Encarnacion, M., Bernales, C.Q. et al. Genetic analysis of nucleotide-binding leucine-rich repeat (NLR) receptors in multiple sclerosis. Immunogenetics 72, 381–385 (2020). https://doi.org/10.1007/s00251-020-01170-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00251-020-01170-w