Absence of Mutation Enrichment for Genes Phylogenetically Conserved in the Olivocerebellar Motor Circuitry in a Cohort of Canadian Essential Tremor Cases
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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.
KeywordsEssential Tremor Movement disorder Genetics Inferior olive Cerebellum
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.
Compliance with Ethical Standards
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.
- 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 2Google 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedPubMedCentralGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedGoogle 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 CrossRefPubMedPubMedCentralGoogle Scholar