Candidate variants in TUB are associated with familial tremor

English version

Autoři: M. Reza Sailani ^aff001; Fereshteh Jahanbani ^aff001; Charles W. Abbott ^aff001; Hayan Lee ^aff001; Amin Zia ^aff001; Shannon Rego ^aff001; Juliane Winkelmann ^aff002; Franziska Hopfner ^aff003; Tahir N. Khan ^aff005; Nicholas Katsanis ^aff005; Stefanie H. Müller ^aff003; Daniela Berg ^aff003; Katherine M. Lyman ^aff001; Christian Mychajliw ^aff009; Günther Deuschl ^aff003; Jonathan A. Bernstein ^aff010; Gregor Kuhlenbäumer ^aff003; Michael P. Snyder ^aff001
Působiště autorů: Department of Genetics, Stanford University, Stanford, CA, United States of America ^aff001; Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, Technical University, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany ^aff002; Department of Neurology, Kiel University, Germany ^aff003; Department of Neurology, Hannover Medical School, Hannover, Germany ^aff004; Center for Human Disease Modeling, Duke University, United States of America ^aff005; Advanced Center for Translational and Genetic Medicine, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital, Chicago, IL, United States of America ^aff006; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States of America ^aff007; Department of Neurology, Universitätsklinikum Tübingen, Germany ^aff008; University Hospital Tübingen, Department of Psychiatry and Psychotherapy, Tübingen, Germany ^aff009; Department of Pediatrics, Stanford University, Stanford, CA, United States of America ^aff010
Vyšlo v časopise: Candidate variants in TUB are associated with familial tremor. PLoS Genet 16(9): e32767. doi:10.1371/journal.pgen.1009010
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009010

Souhrn

Essential tremor (ET) is the most common adult-onset movement disorder. In the present study, we performed whole exome sequencing of a large ET-affected family (10 affected and 6 un-affected family members) and identified a TUB p.V431I variant (rs75594955) segregating in a manner consistent with autosomal-dominant inheritance. Subsequent targeted re-sequencing of TUB in 820 unrelated individuals with sporadic ET and 630 controls revealed significant enrichment of rare nonsynonymous TUB variants (e.g. rs75594955: p.V431I, rs1241709665: p.Ile20Phe, rs55648406: p.Arg49Gln) in the ET cohort (SKAT-O test p-value = 6.20e-08). TUB encodes a transcription factor predominantly expressed in neuronal cells and has been previously implicated in obesity. ChIP-seq analyses of the TUB transcription factor across different regions of the mouse brain revealed that TUB regulates the pathways responsible for neurotransmitter production as well thyroid hormone signaling. Together, these results support the association of rare variants in TUB with ET.

Klíčová slova:

Cerebellum – Hormone receptor signaling – Mammalian genomics – Neostriatum – Polymerase chain reaction – Thyroid hormones – Transcription factors – Myoclonus

Zdroje

1. Louis ED. Essential tremor. Lancet Neurol. 2005;4(2):100–10. Epub 2005/01/25. doi: 10.1016/S1474-4422(05)00991-9 15664542.

2. Higgins JJ, Pho LT, Nee LE. A gene (ETM) for essential tremor maps to chromosome 2p22-p25. Mov Disord. 1997;12(6):859–64. Epub 1997/12/17. doi: 10.1002/mds.870120605 9399207.

3. Elble R, Deuschl G. Milestones in tremor research. Mov Disord. 2011;26(6):1096–105. Epub 2011/06/01. doi: 10.1002/mds.23579 21626554.

4. Muthuraman M, Deuschl G, Anwar AR, Mideksa KG, von Helmolt F, Schneider SA. Essential and aging-related tremor: Differences of central control. Mov Disord. 2015;30(12):1673–80. Epub 2015/09/09. doi: 10.1002/mds.26410 26347194.

5. Deuschl G, Elble R. Essential tremor—neurodegenerative or nondegenerative disease towards a working definition of ET. Mov Disord. 2009;24(14):2033–41. Epub 2009/09/15. doi: 10.1002/mds.22755 19750493.

6. Moghal S, Rajput AH, D'Arcy C, Rajput R. Prevalence of movement disorders in elderly community residents. Neuroepidemiology. 1994;13(4):175–8. Epub 1994/01/01. doi: 10.1159/000110376 8090259.

7. Louis ED, Ferreira JJ. How common is the most common adult movement disorder? Update on the worldwide prevalence of essential tremor. Mov Disord. 2010;25(5):534–41. Epub 2010/02/23. doi: 10.1002/mds.22838 20175185.

8. Tanner CM, Goldman SM, Lyons KE, Aston DA, Tetrud JW, Welsh MD, et al. Essential tremor in twins: an assessment of genetic vs environmental determinants of etiology. Neurology. 2001;57(8):1389–91. Epub 2001/10/24. doi: 10.1212/wnl.57.8.1389 11673577.

9. Merner ND, Girard SL, Catoire H, Bourassa CV, Belzil VV, Riviere JB, et al. Exome sequencing identifies FUS mutations as a cause of essential tremor. Am J Hum Genet. 2012;91(2):313–9. Epub 2012/08/07. doi: 10.1016/j.ajhg.2012.07.002 22863194; PubMed Central PMCID: PMC3415547.

10. Lorenz D, Frederiksen H, Moises H, Kopper F, Deuschl G, Christensen K. High concordance for essential tremor in monozygotic twins of old age. Neurology. 2004;62(2):208–11. Epub 2004/01/28. doi: 10.1212/01.wnl.0000103236.26934.41 14745055.

11. Clark LN, Louis ED. Challenges in essential tremor genetics. Rev Neurol (Paris). 2015;171(6–7):466–74. Epub 2015/05/25. doi: 10.1016/j.neurol.2015.02.015 26003805; PubMed Central PMCID: PMC4863985.

12. Gulcher JR, Jonsson P, Kong A, Kristjansson K, Frigge ML, Karason A, et al. Mapping of a familial essential tremor gene, FET1, to chromosome 3q13. Nat Genet. 1997;17(1):84–7. Epub 1997/09/01. doi: 10.1038/ng0997-84 9288103.

13. Shatunov A, Sambuughin N, Jankovic J, Elble R, Lee HS, Singleton AB, et al. Genomewide scans in North American families reveal genetic linkage of essential tremor to a region on chromosome 6p23. Brain. 2006;129(Pt 9):2318–31. Epub 2006/05/17. doi: 10.1093/brain/awl120 16702189.

14. Jeanneteau F, Funalot B, Jankovic J, Deng H, Lagarde JP, Lucotte G, et al. A functional variant of the dopamine D3 receptor is associated with risk and age-at-onset of essential tremor. Proc Natl Acad Sci U S A. 2006;103(28):10753–8. Epub 2006/07/01. doi: 10.1073/pnas.0508189103 16809426; PubMed Central PMCID: PMC1502303.

15. Thier S, Lorenz D, Nothnagel M, Poremba C, Papengut F, Appenzeller S, et al. Polymorphisms in the glial glutamate transporter SLC1A2 are associated with essential tremor. Neurology. 2012;79(3):243–8. Epub 2012/07/06. doi: 10.1212/WNL.0b013e31825fdeed 22764253; PubMed Central PMCID: PMC3398434.

16. Stefansson H, Steinberg S, Petursson H, Gustafsson O, Gudjonsdottir IH, Jonsdottir GA, et al. Variant in the sequence of the LINGO1 gene confers risk of essential tremor. Nat Genet. 2009;41(3):277–9. Epub 2009/02/03. doi: 10.1038/ng.299 19182806; PubMed Central PMCID: PMC3740956.

17. Muller SH, Girard SL, Hopfner F, Merner ND, Bourassa CV, Lorenz D, et al. Genome-wide association study in essential tremor identifies three new loci. Brain. 2016;139(Pt 12):3163–9. Epub 2016/11/01. doi: 10.1093/brain/aww242 PubMed Central PMCID: PMC5382938. 27797806

18. Liu X, Hernandez N, Kisselev S, Floratos A, Sawle A, Ionita-Laza I, et al. Identification of candidate genes for familial early-onset essential tremor. Eur J Hum Genet. 2016;24(7):1009–15. Epub 2015/10/29. doi: 10.1038/ejhg.2015.228 26508575; PubMed Central PMCID: PMC5070884.

19. Bergareche A, Bednarz M, Sanchez E, Krebs CE, Ruiz-Martinez J, De La Riva P, et al. SCN4A pore mutation pathogenetically contributes to autosomal dominant essential tremor and may increase susceptibility to epilepsy. Hum Mol Genet. 2015;24(24):7111–20. Epub 2015/10/03. doi: 10.1093/hmg/ddv410 26427606; PubMed Central PMCID: PMC4654061.

20. Rajput A, Ross JP, Bernales CQ, Rayaprolu S, Soto-Ortolaza AI, Ross OA, et al. VPS35 and DNAJC13 disease-causing variants in essential tremor. Eur J Hum Genet. 2015;23(6):887–8. Epub 2014/08/15. doi: 10.1038/ejhg.2014.164 25118025; PubMed Central PMCID: PMC4795043.

21. Hor H, Francescatto L, Bartesaghi L, Ortega-Cubero S, Kousi M, Lorenzo-Betancor O, et al. Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor. Hum Mol Genet. 2015;24(20):5677–86. Epub 2015/07/19. doi: 10.1093/hmg/ddv281 26188006; PubMed Central PMCID: PMC4692992.

22. Louis ED, Ottman R. How many people in the USA have essential tremor? Deriving a population estimate based on epidemiological data. Tremor Other Hyperkinet Mov (N Y). 2014;4 : 259. Epub 2014/08/27. doi: 10.7916/D8TT4P4B 25157323; PubMed Central PMCID: PMC4137360.

23. Banda P, Allain TJ. Ward round—seizures, tremor and muscle weakness 20 years after thyroid surgery. Malawi Med J. 2008;20(1):29, 34–5. Epub 2009/03/06. doi: 10.4314/mmj.v20i1.10953 19260445; PubMed Central PMCID: PMC3345656.

24. Liu X, Wu C, Li C, Boerwinkle E. dbNSFP v3.0: A One-Stop Database of Functional Predictions and Annotations for Human Nonsynonymous and Splice-Site SNVs. Hum Mutat. 2016;37(3):235–41. Epub 2015/11/12. doi: 10.1002/humu.22932 26555599; PubMed Central PMCID: PMC4752381.

25. Santagata S, Boggon TJ, Baird CL, Gomez CA, Zhao J, Shan WS, et al. G-protein signaling through tubby proteins. Science. 2001;292(5524):2041–50. Epub 2001/05/26. doi: 10.1126/science.1061233 11375483.

26. Koritschoner NP, Alvarez-Dolado M, Kurz SM, Heikenwalder MF, Hacker C, Vogel F, et al. Thyroid hormone regulates the obesity gene tub. EMBO Rep. 2001;2(6):499–504. Epub 2001/06/21. doi: 10.1093/embo-reports/kve107 11415982; PubMed Central PMCID: PMC1083901.

27. Ikeda A, Nishina PM, Naggert JK. The tubby-like proteins, a family with roles in neuronal development and function. J Cell Sci. 2002;115(Pt 1):9–14. Epub 2002/01/22. 11801719.

28. Deuschl G, Wenzelburger R, Loffler K, Raethjen J, Stolze H. Essential tremor and cerebellar dysfunction clinical and kinematic analysis of intention tremor. Brain. 2000;123 (Pt 8):1568–80. Epub 2000/07/25. doi: 10.1093/brain/123.8.1568 10908187.

29. Parker NF, Cameron CM, Taliaferro JP, Lee J, Choi JY, Davidson TJ, et al. Reward and choice encoding in terminals of midbrain dopamine neurons depends on striatal target. Nat Neurosci. 2016;19(6):845–54. Epub 2016/04/26. doi: 10.1038/nn.4287 27110917; PubMed Central PMCID: PMC4882228.

30. Nishino A, Baba SA, Okamura Y. A mechanism for graded motor control encoded in the channel properties of the muscle ACh receptor. Proc Natl Acad Sci U S A. 2011;108(6):2599–604. Epub 2011/01/26. doi: 10.1073/pnas.1013547108 21262828; PubMed Central PMCID: PMC3038724.

31. Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science. 1976;192(4238):481–3. Epub 1976/04/30. PubMed PMID: 3854. doi: 10.1126/science.3854

32. Graybiel AM. Neurotransmitters and neuromodulators in the basal ganglia. Trends Neurosci. 1990;13(7):244–54. Epub 1990/07/01. doi: 10.1016/0166-2236(90)90104-i 1695398.

33. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG. Dopamine receptors: from structure to function. Physiol Rev. 1998;78(1):189–225. Epub 1998/02/11. doi: 10.1152/physrev.1998.78.1.189 9457173.

34. DeLong MR. Primate models of movement disorders of basal ganglia origin. Trends Neurosci. 1990;13(7):281–5. Epub 1990/07/01. doi: 10.1016/0166-2236(90)90110-v 1695404.

35. Tan EK, Prakash KM, Fook-Chong S, Yih Y, Chua E, Lum SY, et al. DRD3 variant and risk of essential tremor. Neurology. 2007;68(10):790–1. Epub 2007/03/07. doi: 10.1212/01.wnl.0000256773.87498.2f 17339592.

36. Annerbo S, Lokk J. A clinical review of the association of thyroid stimulating hormone and cognitive impairment. ISRN Endocrinol. 2013;2013 : 856017. Epub 2013/10/31. doi: 10.1155/2013/856017 24171118; PubMed Central PMCID: PMC3793467.

37. Bernal J. Thyroid hormone receptors in brain development and function. Nat Clin Pract Endocrinol Metab. 2007;3(3):249–59. Epub 2007/02/23. doi: 10.1038/ncpendmet0424 17315033.

38. Axelrad JE, Louis ED, Honig LS, Flores I, Ross GW, Pahwa R, et al. Reduced Purkinje cell number in essential tremor: a postmortem study. Arch Neurol. 2008;65(1):101–7. Epub 2008/01/16. doi: 10.1001/archneurol.2007.8 18195146; PubMed Central PMCID: PMC2847418.

39. Erickson-Davis CR, Faust PL, Vonsattel JP, Gupta S, Honig LS, Louis ED. "Hairy baskets" associated with degenerative Purkinje cell changes in essential tremor. J Neuropathol Exp Neurol. 2010;69(3):262–71. Epub 2010/02/10. doi: 10.1097/NEN.0b013e3181d1ad04 20142764; PubMed Central PMCID: PMC2865233.

40. Babij R, Lee M, Cortes E, Vonsattel JP, Faust PL, Louis ED. Purkinje cell axonal anatomy: quantifying morphometric changes in essential tremor versus control brains. Brain. 2013;136(Pt 10):3051–61. Epub 2013/09/14. doi: 10.1093/brain/awt238 24030953; PubMed Central PMCID: PMC3784286.

41. Louis ED, Babij R, Lee M, Cortes E, Vonsattel JP. Quantification of cerebellar hemispheric purkinje cell linear density: 32 ET cases versus 16 controls. Mov Disord. 2013;28(13):1854–9. Epub 2013/08/09. doi: 10.1002/mds.25629 23925732; PubMed Central PMCID: PMC3830681.

42. Lin CY, Louis ED, Faust PL, Koeppen AH, Vonsattel JP, Kuo SH. Abnormal climbing fibre-Purkinje cell synaptic connections in the essential tremor cerebellum. Brain. 2014;137(Pt 12):3149–59. Epub 2014/10/03. doi: 10.1093/brain/awu281 25273997; PubMed Central PMCID: PMC4240294.

43. Lam HY, Pan C, Clark MJ, Lacroute P, Chen R, Haraksingh R, et al. Detecting and annotating genetic variations using the HugeSeq pipeline. Nat Biotechnol. 2012;30(3):226–9. Epub 2012/03/09. doi: 10.1038/nbt.2134 22398614; PubMed Central PMCID: PMC4720384.

44. Consortium EP. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489(7414):57–74. Epub 2012/09/08. doi: 10.1038/nature11247 22955616; PubMed Central PMCID: PMC3439153.

45. Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Mov Disord. 1998;13 Suppl 3 : 2–23. Epub 1998/11/25. doi: 10.1002/mds.870131303 9827589.

46. Lee S, Emond MJ, Bamshad MJ, Barnes KC, Rieder MJ, Nickerson DA, et al. Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. Am J Hum Genet. 2012;91(2):224–37. Epub 2012/08/07. doi: 10.1016/j.ajhg.2012.06.007 22863193; PubMed Central PMCID: PMC3415556.

47. Lee S, Wu MC, Lin X. Optimal tests for rare variant effects in sequencing association studies. Biostatistics. 2012;13(4):762–75. Epub 2012/06/16. doi: 10.1093/biostatistics/kxs014 22699862; PubMed Central PMCID: PMC3440237.

48. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9(9):R137. Epub 2008/09/19. doi: 10.1186/gb-2008-9-9-r137 18798982; PubMed Central PMCID: PMC2592715.

49. Ashkenazy H, Abadi S, Martz E, Chay O, Mayrose I, Pupko T, et al. ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules. Nucleic Acids Res. 2016;44(W1):W344–50. Epub 2016/05/12. doi: 10.1093/nar/gkw408 27166375; PubMed Central PMCID: PMC4987940.

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