#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Mineral absorption is an enriched pathway in a brain region of restless legs syndrome patients with reduced MEIS1 expression


Autoři: Faezeh Sarayloo aff001;  Alexandre Dionne-Laporte aff002;  Helene Catoire aff002;  Daniel Rochefort aff002;  Gabrielle Houle aff001;  Jay P. Ross aff001;  Fulya Akçimen aff001;  Rachel De Barros Oliveira aff002;  Gustavo Turecki aff001;  Patrick A. Dion aff002;  Guy A. Rouleau aff002
Působiště autorů: McGill University, Department of Human Genetics, Montréal, QC, Canada aff001;  McGill University, Montreal Neurological Institute, Montréal, QC, Canada aff002;  McGill University, Department of Psychiatry, McGill Group for Suicide Studies, Douglas Institute, Montréal, QC, Canada aff003;  McGill University, Department of Neurology and Neurosurgery, Montréal, QC, Canada aff004
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0225186

Souhrn

Restless legs syndrome is a common complex disorder with different genetic and environmental risk factors. Here we used human cell lines to conduct an RNA-Seq study and observed how the gene showing the most significant association with RLS, MEIS1, acts as a regulator of the expression of many other genes. Some of the genes affected by its expression level are linked to pathways previously reported to be associated with RLS. We found that in cells where MEIS1 expression was either increased or prevented, mineral absorption is the principal dysregulated pathway. The mineral absorption pathway genes, HMOX1 and VDR are involved in iron metabolism and response to vitamin D, respectively. This shows a strong functional link to the known RLS pathways. We observed the same enrichment of the mineral absorption pathway in postmortem brain tissues of RLS patients showing a reduced expression of MEIS1. The expression of genes encoding metallothioneins (MTs) was observed to be dysregulated across the RNA-Seq datasets generated from both human cells and tissues. MTs are highly relevant to RLS as they bind intracellular metals, protect against oxidative stress and interact with ferritins which manage iron level in the central nervous system. Overall, our study suggests that in a subset of RLS patients, the contribution of MEIS1 appears to be associated to its downstream regulation of genes that are more directly involved in pathways that are relevant to RLS. While MTs have been implicated in the pathogenesis of neurodegenerative diseases such as Parkinson’s diseases, this is a first report to propose that they have a role in RLS.

Klíčová slova:

Gene expression – Haplotypes – Gene regulation – Transcription factors – RNA extraction – RNA sequencing – Transcriptional control – Thalamus


Zdroje

1. Dhawan V, Ali M, Chaudhuri KR. Genetic aspects of restless legs syndrome. Postgrad Med J. 2006;82(972):626–9. doi: 10.1136/pgmj.2006.045690 17068272; PubMed Central PMCID: PMC2653903.

2. Desai AV, Cherkas LF, Spector TD, Williams AJ. Genetic influences in self-reported symptoms of obstructive sleep apnoea and restless legs: a twin study. Twin Res. 2004;7(6):589–95. Epub 2004/12/21. doi: 10.1375/1369052042663841 15607009.

3. Xiong L, Jang K, Montplaisir J, Levchenko A, Thibodeau P, Gaspar C, et al. Canadian restless legs syndrome twin study. Neurology. 2007;68(19):1631–3. doi: 10.1212/01.wnl.0000261016.90374.fd 17485653.

4. Desautels A, Turecki G, Montplaisir J, Sequeira A, Verner A, Rouleau GA. Identification of a major susceptibility locus for restless legs syndrome on chromosome 12q. American journal of human genetics. 2001;69(6):1266–70. doi: 10.1086/324649 11704926; PubMed Central PMCID: PMC1235538.

5. Bonati MT, Ferini-Strambi L, Aridon P, Oldani A, Zucconi M, Casari G. Autosomal dominant restless legs syndrome maps on chromosome 14q. Brain: a journal of neurology. 2003;126(Pt 6):1485–92. doi: 10.1093/brain/awg137 12764067.

6. Chen S, Ondo WG, Rao S, Li L, Chen Q, Wang Q. Genomewide linkage scan identifies a novel susceptibility locus for restless legs syndrome on chromosome 9p. American journal of human genetics. 2004;74(5):876–85. doi: 10.1086/420772 15077200; PubMed Central PMCID: PMC1181982.

7. Levchenko A, Provost S, Montplaisir JY, Xiong L, St-Onge J, Thibodeau P, et al. A novel autosomal dominant restless legs syndrome locus maps to chromosome 20p13. Neurology. 2006;67(5):900–1. doi: 10.1212/01.wnl.0000233991.20410.b6 16966564.

8. Pichler I, Marroni F, Volpato CB, Gusella JF, Klein C, Casari G, et al. Linkage analysis identifies a novel locus for restless legs syndrome on chromosome 2q in a South Tyrolean population isolate. American journal of human genetics. 2006;79(4):716–23. doi: 10.1086/507875 16960808; PubMed Central PMCID: PMC1592574.

9. Kemlink D, Plazzi G, Vetrugno R, Provini F, Polo O, Stiasny-Kolster K, et al. Suggestive evidence for linkage for restless legs syndrome on chromosome 19p13. Neurogenetics. 2008;9(2):75–82. doi: 10.1007/s10048-007-0113-1 18193462; PubMed Central PMCID: PMC2757615.

10. Levchenko A, Montplaisir JY, Asselin G, Provost S, Girard SL, Xiong L, et al. Autosomal-dominant locus for Restless Legs Syndrome in French-Canadians on chromosome 16p12.1. Movement disorders: official journal of the Movement Disorder Society. 2009;24(1):40–50. doi: 10.1002/mds.22263 18946881.

11. Winkelmann J, Czamara D, Schormair B, Knauf F, Schulte EC, Trenkwalder C, et al. Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1. PLoS genetics. 2011;7(7):e1002171. doi: 10.1371/journal.pgen.1002171 21779176; PubMed Central PMCID: PMC3136436.

12. Schormair B, Zhao C, Bell S, Tilch E, Salminen AV, Putz B, et al. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis. The Lancet Neurology. 2017;16(11):898–907. doi: 10.1016/S1474-4422(17)30327-7 29029846; PubMed Central PMCID: PMC5755468.

13. Winkelmann J. Genetics of restless legs syndrome. Current neurology and neuroscience reports. 2008;8(3):211–6. 18541116.

14. Allen RP, Earley CJ. The role of iron in restless legs syndrome. Movement disorders: official journal of the Movement Disorder Society. 2007;22 Suppl 18:S440–8. doi: 10.1002/mds.21607 17566122.

15. Ondo W, Romanyshyn J, Vuong KD, Lai D. Long-term treatment of restless legs syndrome with dopamine agonists. Archives of neurology. 2004;61(9):1393–7. doi: 10.1001/archneur.61.9.1393 15364685.

16. Trenkwalder C, Allen R, Hogl B, Paulus W, Winkelmann J. Restless legs syndrome associated with major diseases: A systematic review and new concept. Neurology. 2016;86(14):1336–43. doi: 10.1212/WNL.0000000000002542 26944272; PubMed Central PMCID: PMC4826337.

17. Wali S, Shukr A, Boudal A, Alsaiari A, Krayem A. The effect of vitamin D supplements on the severity of restless legs syndrome. Sleep & breathing = Schlaf & Atmung. 2015;19(2):579–83. doi: 10.1007/s11325-014-1049-y 25148866.

18. Catoire H, Sarayloo F, Mourabit Amari K, Apuzzo S, Grant A, Rochefort D, et al. A direct interaction between two Restless Legs Syndrome predisposing genes: MEIS1 and SKOR1. Scientific reports. 2018;8(1):12173. doi: 10.1038/s41598-018-30665-6 30111810; PubMed Central PMCID: PMC6093889.

19. Biedler JL, Helson L, Spengler BA. Morphology and growth, tumorigenicity, and cytogenetics of human neuroblastoma cells in continuous culture. Cancer Res. 1973;33(11):2643–52. Epub 1973/11/01. 4748425.

20. Xiong L, Catoire H, Dion P, Gaspar C, Lafreniere RG, Girard SL, et al. MEIS1 intronic risk haplotype associated with restless legs syndrome affects its mRNA and protein expression levels. Human molecular genetics. 2009;18(6):1065–74. doi: 10.1093/hmg/ddn443 19126776; PubMed Central PMCID: PMC2722232.

21. Sarayloo F, Dion PA, Rouleau GA. MEIS1 and Restless Legs Syndrome: A Comprehensive Review. Front Neurol. 2019;10:935. Epub 2019/09/26. doi: 10.3389/fneur.2019.00935 31551905; PubMed Central PMCID: PMC6736557.

22. Vasconcelos FF, Sessa A, Laranjeira C, Raposo A, Teixeira V, Hagey DW, et al. MyT1 Counteracts the Neural Progenitor Program to Promote Vertebrate Neurogenesis. Cell reports. 2016;17(2):469–83. doi: 10.1016/j.celrep.2016.09.024 27705795; PubMed Central PMCID: PMC5067283.

23. Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(16):6062–7. doi: 10.1073/pnas.0400782101 15075390; PubMed Central PMCID: PMC395923.

24. Godau J, Klose U, Di Santo A, Schweitzer K, Berg D. Multiregional brain iron deficiency in restless legs syndrome. Movement disorders: official journal of the Movement Disorder Society. 2008;23(8):1184–7. doi: 10.1002/mds.22070 18442125.

25. Koo BB, Bagai K, Walters AS. Restless Legs Syndrome: Current Concepts about Disease Pathophysiology. Tremor Other Hyperkinet Mov (N Y). 2016;6:401. doi: 10.7916/D83J3D2G 27536462; PubMed Central PMCID: PMC4961894.

26. Catoire H, Dion PA, Xiong L, Amari M, Gaudet R, Girard SL, et al. Restless legs syndrome-associated MEIS1 risk variant influences iron homeostasis. Annals of neurology. 2011;70(1):170–5. doi: 10.1002/ana.22435 21710629.

27. Chen EY, Tan CM, Kou Y, Duan Q, Wang Z, Meirelles GV, et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC bioinformatics. 2013;14:128. doi: 10.1186/1471-2105-14-128 23586463; PubMed Central PMCID: PMC3637064.

28. Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic acids research. 2016;44(W1):W90–7. doi: 10.1093/nar/gkw377 27141961; PubMed Central PMCID: PMC4987924.

29. Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature protocols. 2009;4(1):44–57. doi: 10.1038/nprot.2008.211 19131956.

30. Huang da W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic acids research. 2009;37(1):1–13. doi: 10.1093/nar/gkn923 19033363; PubMed Central PMCID: PMC2615629.

31. Garcia-Martin E, Jimenez-Jimenez FJ, Alonso-Navarro H, Martinez C, Zurdo M, Turpin-Fenoll L, et al. Heme Oxygenase-1 and 2 Common Genetic Variants and Risk for Restless Legs Syndrome. Medicine. 2015;94(34):e1448. doi: 10.1097/MD.0000000000001448 26313808; PubMed Central PMCID: PMC4602895.

32. Jimenez-Jimenez FJ, Garcia-Martin E, Alonso-Navarro H, Martinez C, Zurdo M, Turpin-Fenoll L, et al. Association Between Vitamin D Receptor rs731236 (Taq1) Polymorphism and Risk for Restless Legs Syndrome in the Spanish Caucasian Population. Medicine. 2015;94(47):e2125. Epub 2015/12/04. doi: 10.1097/MD.0000000000002125 26632733; PubMed Central PMCID: PMC5059002.

33. Balaban H, Yildiz OK, Cil G, Senturk IA, Erselcan T, Bolayir E, et al. Serum 25-hydroxyvitamin D levels in restless legs syndrome patients. Sleep medicine. 2012;13(7):953–7. doi: 10.1016/j.sleep.2012.04.009 22704399.

34. Cakir T, Dogan G, Subasi V, Filiz MB, Ulker N, Dogan SK, et al. An evaluation of sleep quality and the prevalence of restless leg syndrome in vitamin D deficiency. Acta neurologica Belgica. 2015;115(4):623–7. doi: 10.1007/s13760-015-0474-4 25904436.

35. Juarez-Rebollar D, Rios C, Nava-Ruiz C, Mendez-Armenta M. Metallothionein in Brain Disorders. Oxid Med Cell Longev. 2017;2017:5828056. Epub 2017/11/01. doi: 10.1155/2017/5828056 29085556; PubMed Central PMCID: PMC5632493.

36. Mahe EA, Madigou T, Serandour AA, Bizot M, Avner S, Chalmel F, et al. Cytosine modifications modulate the chromatin architecture of transcriptional enhancers. Genome research. 2017;27(6):947–58. doi: 10.1101/gr.211466.116 28396520; PubMed Central PMCID: PMC5453328.

37. Karayannis T, Au E, Patel JC, Kruglikov I, Markx S, Delorme R, et al. Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission. Nature. 2014;511(7508):236–40. doi: 10.1038/nature13248 24870235; PubMed Central PMCID: PMC4281262.

38. Sleeman MW, Anderson KD, Lambert PD, Yancopoulos GD, Wiegand SJ. The ciliary neurotrophic factor and its receptor, CNTFR alpha. Pharm Acta Helv. 2000;74(2–3):265–72. Epub 2000/05/17. doi: 10.1016/s0031-6865(99)00050-3 10812968.

39. Rogers PM, Ying L, Burris TP. Relationship between circadian oscillations of Rev-erbalpha expression and intracellular levels of its ligand, heme. Biochem Biophys Res Commun. 2008;368(4):955–8. Epub 2008/02/19. doi: 10.1016/j.bbrc.2008.02.031 18280802; PubMed Central PMCID: PMC2746331.

40. Yin L, Wu N, Lazar MA. Nuclear receptor Rev-erbalpha: a heme receptor that coordinates circadian rhythm and metabolism. Nucl Recept Signal. 2010;8:e001. Epub 2010/04/24. doi: 10.1621/nrs.08001 20414452; PubMed Central PMCID: PMC2858265.

41. Mizuhara E, Nakatani T, Minaki Y, Sakamoto Y, Ono Y. Corl1, a novel neuronal lineage-specific transcriptional corepressor for the homeodomain transcription factor Lbx1. The Journal of biological chemistry. 2005;280(5):3645–55. doi: 10.1074/jbc.M411652200 15528197.

42. Miyazaki I, Asanuma M, Murakami S, Takeshima M, Torigoe N, Kitamura Y, et al. Targeting 5-HT(1A) receptors in astrocytes to protect dopaminergic neurons in Parkinsonian models. Neurobiol Dis. 2013;59:244–56. Epub 2013/08/21. doi: 10.1016/j.nbd.2013.08.003 23959140.

43. Orihuela R, Fernandez B, Palacios O, Valero E, Atrian S, Watt RK, et al. Ferritin and metallothionein: dangerous liaisons. Chem Commun (Camb). 2011;47(44):12155–7. doi: 10.1039/c1cc14819b 21991581.

44. Robertson A, Morrison JN, Wood AM, Bremner I. Effects of iron deficiency on metallothionein-I concentrations in blood and tissues of rats. J Nutr. 1989;119(3):439–45. Epub 1989/03/01. doi: 10.1093/jn/119.3.439 2921643.

45. Leierer J, Rudnicki M, Braniff SJ, Perco P, Koppelstaetter C, Muhlberger I, et al. Metallothioneins and renal ageing. Nephrology, dialysis, transplantation: official publication of the wEuropean Dialysis and Transplant Association—European Renal Association. 2016;31(9):1444–52. Epub 2016/02/26. doi: 10.1093/ndt/gfv451 26908771.

46. Novak M, Winkelman JW, Unruh M. Restless Legs Syndrome in Patients With Chronic Kidney Disease. Seminars in nephrology. 2015;35(4):347–58. doi: 10.1016/j.semnephrol.2015.06.006 26355253.

47. Garcia-Borreguero D, Silber MH, Winkelman JW, Hogl B, Bainbridge J, Buchfuhrer M, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep medicine. 2016;21:1–11. Epub 2016/07/28. doi: 10.1016/j.sleep.2016.01.017 27448465.

48. Schuierer S, Carbone W, Knehr J, Petitjean V, Fernandez A, Sultan M, et al. A comprehensive assessment of RNA-seq protocols for degraded and low-quantity samples. BMC genomics. 2017;18(1):442. Epub 2017/06/07. doi: 10.1186/s12864-017-3827-y 28583074; PubMed Central PMCID: PMC5460543.

49. Cieslik M, Chugh R, Wu YM, Wu M, Brennan C, Lonigro R, et al. The use of exome capture RNA-seq for highly degraded RNA with application to clinical cancer sequencing. Genome research. 2015;25(9):1372–81. doi: 10.1101/gr.189621.115 26253700; PubMed Central PMCID: PMC4561495.

50. Wang Z, Gerstein M, Snyder M. RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet. 2009;10(1):57–63. Epub 2008/11/19. nrg2484 [pii] doi: 10.1038/nrg2484 19015660; PubMed Central PMCID: PMC2949280.

51. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15–21. doi: 10.1093/bioinformatics/bts635 23104886; PubMed Central PMCID: PMC3530905.

52. Trapnell C, Roberts A, Goff L, Pertea G, Kim D, Kelley DR, et al. Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nature protocols. 2012;7(3):562–78. doi: 10.1038/nprot.2012.016 22383036; PubMed Central PMCID: PMC3334321.

53. Bourgey M, Dali R, Eveleigh R, Chen KC, Letourneau L, Fillon J, et al. GenPipes: an open-source framework for distributed and scalable genomic analyses. Gigascience. 2019;8(6). Epub 2019/06/12. doi: 10.1093/gigascience/giz037 31185495; PubMed Central PMCID: PMC6559338.

54. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–40. doi: 10.1093/bioinformatics/btp616 19910308; PubMed Central PMCID: PMC2796818.

55. Gallego Romero I, Pai AA, Tung J, Gilad Y. RNA-seq: impact of RNA degradation on transcript quantification. BMC Biol. 2014;12:42. Epub 2014/06/03. doi: 10.1186/1741-7007-12-42 24885439; PubMed Central PMCID: PMC4071332.


Článok vyšiel v časopise

PLOS One


2019 Číslo 11
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#