Skip to main content
SpringerLink
Log in

Absence of Mutation Enrichment for Genes Phylogenetically Conserved in the Olivocerebellar Motor Circuitry in a Cohort of Canadian Essential Tremor Cases

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Essential Tremor is a prevalent neurological disorder of unknown etiology. Studies suggest that genetic factors contribute to this pathology. To date, no causative mutations in a gene have been reproducibly reported. All three structures of the olivocerebellar motor circuitry have been linked to Essential Tremor. We postulated that genes enriched for their expression in the olivocerebellar circuitry would be more susceptible to harbor mutations in Essential Tremor patients. A list of 11 candidate genes, enriched for their expression in the olivocerebellar circuitry, was assessed for their variation spectrum and frequency in a cohort of Canadian Essential Tremor cases. Our results from this list of 11 candidate genes do not support an association for Essential Tremor in our cohort of Canadian cases. The heterogenic nature of ET and modest size of the cohort used in this study are two confounding factors that could explain these results.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Deuschl G, Bain P, Brin M (1998) Consensus statement of the Movement Disorder Society on tremor. Ad hoc scientific committee. Mov Disord 13(Suppl 3):2–23

    PubMed  Google Scholar 

  2. Louis ED, Ferreira JJ (2010) How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Mov Disord 25(5):534–541. https://doi.org/10.1002/mds.22838

    Article  PubMed  Google Scholar 

  3. Tanner CM, Goldman SM, Lyons KE, Aston DA, Tetrud JW, Welsh MD, Langston JW, Koller WC (2001) Essential tremor in twins: an assessment of genetic vs environmental determinants of etiology. Neurology 57(8):1389–1391

    Article  CAS  PubMed  Google Scholar 

  4. Lorenz D, Frederiksen H, Moises H, Kopper F, Deuschl G, Christensen K (2004) High concordance for essential tremor in monozygotic twins of old age. Neurology 62(2):208–211

    Article  CAS  PubMed  Google Scholar 

  5. Schmouth JF, Dion PA, Rouleau GA (2014) Genetics of essential tremor: from phenotype to genes, insights from both human and mouse studies. Prog Neurobiol 119-120:1–19. https://doi.org/10.1016/j.pneurobio.2014.05.001

    Article  CAS  PubMed  Google Scholar 

  6. Bares M, Husarova I, Lungu OV (2012) Essential tremor, the cerebellum, and motor timing: towards integrating them into one complex entity. Tremor Other Hyperkinet Mov 2

  7. de Montigny C, Lamarre Y (1973) Rhythmic activity induced by harmaline in the olivo-cerebello-bulbar system of the cat. Brain Res 53(1):81–95

    Article  PubMed  Google Scholar 

  8. Park YG, Park HY, Lee CJ, Choi S, Jo S, Choi H, Kim YH, Shin HS et al (2010) Ca(V)3.1 is a tremor rhythm pacemaker in the inferior olive. Proc Natl Acad Sci U S A 107(23):10731–10736. https://doi.org/10.1073/pnas.1002995107

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kralic JE, Criswell HE, Osterman JL, O'Buckley TK, Wilkie ME, Matthews DB, Hamre K, Breese GR et al (2005) Genetic essential tremor in gamma-aminobutyric acidA receptor alpha1 subunit knockout mice. J Clin Invest 115(3):774–779. https://doi.org/10.1172/JCI23625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Boecker H, Wills AJ, Ceballos-Baumann A, Samuel M, Thompson PD, Findley LJ, Brooks DJ (1996) The effect of ethanol on alcohol-responsive essential tremor: a positron emission tomography study. Ann Neurol 39(5):650–658. https://doi.org/10.1002/ana.410390515

    Article  CAS  PubMed  Google Scholar 

  11. Paris-Robidas S, Brochu E, Sintes M, Emond V, Bousquet M, Vandal M, Pilote M, Tremblay C et al (2012) Defective dentate nucleus GABA receptors in essential tremor. Brain 135(Pt 1):105–116. https://doi.org/10.1093/brain/awr301

    Article  PubMed  Google Scholar 

  12. Louis ED, Faust PL, Vonsattel JP, Honig LS, Rajput A, Robinson CA, Pahwa R, Lyons KE et al (2007) Neuropathological changes in essential tremor: 33 cases compared with 21 controls. Brain 130(Pt 12):3297–3307. https://doi.org/10.1093/brain/awm266

    Article  PubMed  Google Scholar 

  13. Babij R, Lee M, Cortes E, Vonsattel JP, Faust PL, Louis ED (2013) Purkinje cell axonal anatomy: quantifying morphometric changes in essential tremor versus control brains. Brain 136(Pt 10):3051–3061. https://doi.org/10.1093/brain/awt238

    Article  PubMed  PubMed Central  Google Scholar 

  14. Louis ED, Babij R, Lee M, Cortes E, Vonsattel JP (2013) Quantification of cerebellar hemispheric purkinje cell linear density: 32 ET cases versus 16 controls. Mov Disord 28(13):1854–1859. https://doi.org/10.1002/mds.25629

    Article  PubMed  Google Scholar 

  15. Erickson-Davis CR, Faust PL, Vonsattel JP, Gupta S, Honig LS, Louis ED (2010) “Hairy baskets” associated with degenerative Purkinje cell changes in essential tremor. J Neuropathol Exp Neurol 69(3):262–271. https://doi.org/10.1097/NEN.0b013e3181d1ad04

    Article  PubMed  Google Scholar 

  16. Louis ED (2015) Linking essential tremor to the cerebellum: neuropathological evidence. Cerebellum 15:235–242. https://doi.org/10.1007/s12311-015-0692-6

    Article  Google Scholar 

  17. Benito-Leon J, Labiano-Fontcuberta A (2016) Linking essential tremor to the cerebellum: clinical evidence. Cerebellum 15(3):253–262. https://doi.org/10.1007/s12311-015-0741-1

    Article  PubMed  Google Scholar 

  18. Filip P, Lungu OV, Manto MU, Bares M (2016) Linking essential tremor to the cerebellum: physiological evidence. Cerebellum 15(6):774–780. https://doi.org/10.1007/s12311-015-0740-2

    Article  PubMed  Google Scholar 

  19. Schrag A, Munchau A, Bhatia KP, Quinn NP, Marsden CD (2000) Essential tremor: an overdiagnosed condition? J Neurol 247(12):955–959

    Article  CAS  PubMed  Google Scholar 

  20. Houle G, Schmouth JF, Leblond CS, Ambalavanan A, Spiegelman D, Laurent SB, Bourassa CV, Panisset M et al (2017) Teneurin transmembrane protein 4 is not a cause for essential tremor in a Canadian population. Mov Disord 32:292–295. https://doi.org/10.1002/mds.26753

    Article  CAS  PubMed  Google Scholar 

  21. Ng L, Bernard A, Lau C, Overly CC, Dong HW, Kuan C, Pathak S, Sunkin SM et al (2009) An anatomic gene expression atlas of the adult mouse brain. Nat Neurosci 12(3):356–362. https://doi.org/10.1038/nn.2281

    Article  CAS  PubMed  Google Scholar 

  22. Huang da W, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4(1):44–57. https://doi.org/10.1038/nprot.2008.211

    Article  CAS  PubMed  Google Scholar 

  23. Schmouth JF, Arenillas D, Corso-Diaz X, Xie YY, Bohacec S, Banks KG, Bonaguro RJ, Wong SH et al (2015) Combined serial analysis of gene expression and transcription factor binding site prediction identifies novel-candidate-target genes of Nr2e1 in neocortex development. BMC Genomics 16:545. https://doi.org/10.1186/s12864-015-1770-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. O'Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, Carvill G, Kumar A et al (2012) Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338(6114):1619–1622. https://doi.org/10.1126/science.1227764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wu MC, Kraft P, Epstein MP, Taylor DM, Chanock SJ, Hunter DJ, Lin X (2010) Powerful SNP-set analysis for case-control genome-wide association studies. Am J Hum Genet 86(6):929–942. https://doi.org/10.1016/j.ajhg.2010.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wu MC, Lee S, Cai T, Li Y, Boehnke M, Lin X (2011) Rare-variant association testing for sequencing data with the sequence kernel association test. Am J Hum Genet 89(1):82–93. https://doi.org/10.1016/j.ajhg.2011.05.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lee S, Emond MJ, Bamshad MJ, Barnes KC, Rieder MJ, Nickerson DA, Christiani DC, Wurfel MM et al (2012) Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. Am J Hum Genet 91(2):224–237. https://doi.org/10.1016/j.ajhg.2012.06.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA (2003) DAVID: database for annotation, visualization, and integrated discovery. Genome Biol 4(5):P3

    Article  PubMed  Google Scholar 

  29. Huguenard JR (1996) Low-threshold calcium currents in central nervous system neurons. Annu Rev Physiol 58:329–348. https://doi.org/10.1146/annurev.ph.58.030196.001553

    Article  CAS  PubMed  Google Scholar 

  30. Kim D, Song I, Keum S, Lee T, Jeong MJ, Kim SS, McEnery MW, Shin HS (2001) Lack of the burst firing of thalamocortical relay neurons and resistance to absence seizures in mice lacking alpha(1G) T-type Ca(2+) channels. Neuron 31(1):35–45

    Article  CAS  PubMed  Google Scholar 

  31. McCormick DA, Bal T (1997) Sleep and arousal: thalamocortical mechanisms. Annu Rev Neurosci 20:185–215. https://doi.org/10.1146/annurev.neuro.20.1.185

    Article  CAS  PubMed  Google Scholar 

  32. Du W, Aloyo VJ, Harvey JA (1997) Harmaline competitively inhibits [3H]MK-801 binding to the NMDA receptor in rabbit brain. Brain Res 770(1–2):26–29

    Article  CAS  PubMed  Google Scholar 

  33. O'Hearn E, Molliver ME (2004) Administration of a non-NMDA antagonist, GYKI 52466, increases excitotoxic Purkinje cell degeneration caused by ibogaine. Neuroscience 127(2):373–383. https://doi.org/10.1016/j.neuroscience.2004.04.058

    Article  CAS  PubMed  Google Scholar 

  34. Lin CY, Louis ED, Faust PL, Koeppen AH, Vonsattel JP, Kuo SH (2014) Abnormal climbing fibre-Purkinje cell synaptic connections in the essential tremor cerebellum. Brain 137(Pt 12):3149–3159. https://doi.org/10.1093/brain/awu281

    Article  PubMed  PubMed Central  Google Scholar 

  35. Wang J, Kelly GC, Tate WJ, Li YS, Lee M, Gutierrez J, Louis ED, Faust PL et al (2016) Excitatory amino acid transporter expression in the essential tremor dentate nucleus and cerebellar cortex: a postmortem study. Parkinsonism Relat Disord 32:87–93. https://doi.org/10.1016/j.parkreldis.2016.09.003

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

G.A.R. is supported by the Canadian Institutes of Health Research Foundation Scheme grants (#332971) and holds a Canada Research Chair in Genetics of the Nervous System and the Wilder Penfield Chair in Neurosciences.

J.F.S. had a fellowship from the Canadian Institute of Health Research.

G.H. is the recipient from a Gerard Bouchard scholarship from the Réseau de Médecine Génétique Appliqué (RMGA).

C.S.L was the recipient of a Tim E. Noël fellowship from ALS Canada.

Author information

Authors and Affiliations

  1. Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

    Jean-François Schmouth, Patrick A. Dion & Guy A. Rouleau

  2. Montreal Neurological Institute and Hospital, 3801 University Street, Montreal, QC, H3A 2B4, Canada

    Jean-François Schmouth, Gabrielle Houle, Amirthagowri Ambalavanan, Claire S. Leblond, Dan Spiegelman, Sandra B. Laurent, Cynthia V. Bourassa, Patrick A. Dion & Guy A. Rouleau

  3. Department of Human Genetics, McGill University, Montreal, QC, Canada

    Gabrielle Houle, Amirthagowri Ambalavanan, Claire S. Leblond & Guy A. Rouleau

  4. Centre Hospitalier Universitaire de Montréal-Hotel Dieu, Movement Disorders Unit, CHUM, Montreal, Quebec, Canada

    Michel Panisset & Sylvain Chouinard

  5. Department of Medicine, Faculty of Medicine, Laval University, Quebec City, QC, Canada

    Nicolas Dupré

  6. Département des Sciences Neurologiques, CHU de Québec (Enfant-Jésus), Quebec City, QC, Canada

    Nicolas Dupré

  7. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

    Carles Vilariño-Güell

  8. Division of Neurology, Saskatchewan Movement Disorders Program, University of Saskatchewan, Saskatoon Health Region, Saskatoon, SK, Canada

    Alex Rajput

Authors
  1. Jean-François Schmouth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gabrielle Houle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amirthagowri Ambalavanan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Claire S. Leblond
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dan Spiegelman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sandra B. Laurent
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cynthia V. Bourassa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michel Panisset
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sylvain Chouinard
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nicolas Dupré
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Carles Vilariño-Güell
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Alex Rajput
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Patrick A. Dion
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Guy A. Rouleau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guy A. Rouleau.

Ethics declarations

Ethics approval for the recruitment and genetic analysis of ET-affected individuals and their families has been granted at the following institutes: MUHC (McGill University Health Centre) (Roubank protocol no.: 14051), CRCHUM (Centre de recherche du Centre hospitalier de l’Université de Montréal) (project no.: ND043076).

Conflict of Interest

The authors declare that they have no conflict of interest.

Electronic Supplementary Material

ESM 1

(DOCX 26 kb)

ESM 2

(DOCX 27 kb)

ESM 3

(DOCX 14 kb)

ESM 4

(DOCX 14 kb)

ESM 5

(DOCX 14 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schmouth, JF., Houle, G., Ambalavanan, A. et al. Absence of Mutation Enrichment for Genes Phylogenetically Conserved in the Olivocerebellar Motor Circuitry in a Cohort of Canadian Essential Tremor Cases. Mol Neurobiol 56, 4317–4321 (2019). https://doi.org/10.1007/s12035-018-1369-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-018-1369-1

Keywords

Search

Navigation