Suppression of Somatic Expansion Delays the Onset of Pathophysiology in a Mouse Model of Huntington’s Disease

1. McMurray CT. Mechanisms of trinucleotide repeat instability during human development. Nature reviews Genetics. 2010;11(11):786–99. Epub 2010/10/19. doi: 10.1038/nrg2828 20953213

2. Mirkin SM. Expandable DNA repeats and human disease. Nature. 2007;447(7147):932–40. Epub 2007/06/22. 17581576

3. Lopez Castel A, Cleary JD, Pearson CE. Repeat instability as the basis for human diseases and as a potential target for therapy. Nat Rev Mol Cell Biol. 2010;11(3):165–70. Epub 2010/02/24. doi: 10.1038/nrm2854 20177394

4. Telenius H, Kremer B, Goldberg YP, Theilmann J, Andrew SE, Zeisler J, et al. Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm. Nat Genet. 1994;6(4):409–14. Epub 1994/04/01. 8054984

5. De Rooij KE, De Koning Gans PA, Roos RA, Van Ommen GJ, Den Dunnen JT. Somatic expansion of the (CAG)n repeat in Huntington disease brains. Human genetics. 1995;95(3):270–4. Epub 1995/03/01. 7868117

6. Aronin N, Chase K, Young C, Sapp E, Schwarz C, Matta N, et al. CAG expansion affects the expression of mutant Huntingtin in the Huntington's disease brain. Neuron. 1995;15(5):1193–201. Epub 1995/11/01. 7576661

7. Giovannone B, Sabbadini G, Di Maio L, Calabrese O, Castaldo I, Frontali M, et al. Analysis of (CAG)n size heterogeneity in somatic and sperm cell DNA from intermediate and expanded Huntington disease gene carriers. Hum Mutat. 1997;10(6):458–64. Epub 1997/01/01. 9401009

8. Kahlem P, Djian P. The expanded CAG repeat associated with juvenile Huntington disease shows a common origin of most or all neurons and glia in human cerebrum. Neurosci Lett. 2000;286(3):203–7. Epub 2000/06/01. 10832020

9. Duyao M, Ambrose C, Myers R, Novelletto A, Persichetti F, Frontali M, et al. Trinucleotide repeat length instability and age of onset in Huntington's disease. Nat Genet. 1993;4(4):387–92. Epub 1993/08/01. 8401587

10. Norremolle A, Hasholt L, Petersen CB, Eiberg H, Hasselbalch SG, Gideon P, et al. Mosaicism of the CAG repeat sequence in the Huntington disease gene in a pair of monozygotic twins. American journal of medical genetics Part A. 2004;130A(2):154–9. Epub 2004/09/17. 15372528

11. Kennedy L, Shelbourne PF. Dramatic mutation instability in HD mouse striatum: does polyglutamine load contribute to cell-specific vulnerability in Huntington's disease? Human molecular genetics. 2000;9(17):2539–44. Epub 2000/10/13. 11030759

12. Kennedy L, Evans E, Chen CM, Craven L, Detloff PJ, Ennis M, et al. Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. Human molecular genetics. 2003;12(24):3359–67. Epub 2003/10/23. 14570710

13. Swami M, Hendricks AE, Gillis T, Massood T, Mysore J, Myers RH, et al. Somatic expansion of the Huntington's disease CAG repeat in the brain is associated with an earlier age of disease onset. Human molecular genetics. 2009;18(16):3039–47. Epub 2009/05/26. doi: 10.1093/hmg/ddp242 19465745

14. Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, Adam S, et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat Genet. 1993;4(4):398–403. Epub 1993/08/01. 8401589

15. Mangiarini L, Sathasivam K, Mahal A, Mott R, Seller M, Bates GP. Instability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutation. Nat Genet. 1997;15(2):197–200. Epub 1997/02/01. 9020849

16. Wheeler VC, Auerbach W, White JK, Srinidhi J, Auerbach A, Ryan A, et al. Length-dependent gametic CAG repeat instability in the Huntington's disease knock-in mouse. Human molecular genetics. 1999;8(1):115–22. Epub 1999/01/15. 9887339

17. Ishiguro H, Yamada K, Sawada H, Nishii K, Ichino N, Sawada M, et al. Age-dependent and tissue-specific CAG repeat instability occurs in mouse knock-in for a mutant Huntington's disease gene. Journal of neuroscience research. 2001;65(4):289–97. Epub 2001/08/09. 11494364

18. Lee JM, Pinto RM, Gillis T, St Claire JC, Wheeler VC. Quantification of age-dependent somatic CAG repeat instability in Hdh CAG knock-in mice reveals different expansion dynamics in striatum and liver. PLoS One. 2011;6(8):e23647. Epub 2011/09/08. doi: 10.1371/journal.pone.0023647 21897851

19. Kovtun IV, Liu Y, Bjoras M, Klungland A, Wilson SH, McMurray CT. OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature. 2007;447(7143):447–52. Epub 2007/04/24. 17450122

20. Lin CH, Tallaksen-Greene S, Chien WM, Cearley JA, Jackson WS, Crouse AB, et al. Neurological abnormalities in a knock-in mouse model of Huntington's disease. Human molecular genetics. 2001;10(2):137–44. Epub 2001/01/12. 11152661

21. Klungland A, Rosewell I, Hollenbach S, Larsen E, Daly G, Epe B, et al. Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage. Proc Natl Acad Sci U S A. 1999;96(23):13300–5. Epub 1999/11/11. 10557315

22. Arai T, Kelly VP, Minowa O, Noda T, Nishimura S. The study using wild-type and Ogg1 knockout mice exposed to potassium bromate shows no tumor induction despite an extensive accumulation of 8-hydroxyguanine in kidney DNA. Toxicology. 2006;221(2–3):179–86. Epub 2006/02/24. 16494984

23. Stuart JA, Bourque BM, de Souza-Pinto NC, Bohr VA. No evidence of mitochondrial respiratory dysfunction in OGG1-null mice deficient in removal of 8-oxodeoxyguanine from mitochondrial DNA. Free Radic Biol Med. 2005;38(6):737–45. Epub 2005/02/22. 15721984

24. Andresen JM, Gayan J, Djousse L, Roberts S, Brocklebank D, Cherny SS, et al. The relationship between CAG repeat length and age of onset differs for Huntington's disease patients with juvenile onset or adult onset. Ann Hum Genet. 2007;71(Pt 3):295–301. Epub 2006/12/22. 17181545

25. Gayan J, Brocklebank D, Andresen JM, Alkorta-Aranburu G, Zameel Cader M, Roberts SA, et al. Genomewide linkage scan reveals novel loci modifying age of onset of Huntington's disease in the Venezuelan HD kindreds. Genetic epidemiology. 2008;32(5):445–53. Epub 2008/05/17. doi: 10.1002/gepi.20317 18481795

26. Li JL, Hayden MR, Almqvist EW, Brinkman RR, Durr A, Dode C, et al. A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study. Am J Hum Genet. 2003;73(3):682–7. Epub 2003/08/06. 12900792

27. Arning L, Monte D, Hansen W, Wieczorek S, Jagiello P, Akkad DA, et al. ASK1 and MAP2K6 as modifiers of age at onset in Huntington's disease. J Mol Med (Berl). 2008;86(4):485–90. Epub 2008/03/11.

28. Li JL, Hayden MR, Warby SC, Durr A, Morrison PJ, Nance M, et al. Genome-wide significance for a modifier of age at neurological onset in Huntington's disease at 6q23-24: the HD MAPS study. BMC medical genetics. 2006;7 : 71. Epub 2006/08/18. 16914060

29. Djousse L, Knowlton B, Hayden MR, Almqvist EW, Brinkman RR, Ross CA, et al. Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16. Neurogenetics. 2004;5(2):109–14. Epub 2004/03/19. 15029481

30. Kovtun IV, McMurray CT. Trinucleotide expansion in haploid germ cells by gap repair. Nat Genet. 2001;27(4):407–11. Epub 2001/03/30. 11279522

31. Brooks SP, Dunnett SB. Tests to assess motor phenotype in mice: a user's guide. Nature reviews Neuroscience. 2009;10(7):519–29. Epub 2009/06/11. doi: 10.1038/nrn2652 19513088

32. Cohen M, Dalal SR, Tukey JW. Robust, Smoothly Heterogeneous Variance Regression. Appl Stat-J Roy St C. 1993;42(2):339–53.

33. Mollersen L, Rowe AD, Illuzzi JL, Hildrestrand GA, Gerhold KJ, Tveteras L, et al. Neil1 is a genetic modifier of somatic and germline CAG trinucleotide repeat instability in R6/1 mice. Human molecular genetics. 2012. Epub 2012/08/24.

34. Hubert L Jr., Lin Y, Dion V, Wilson JH. Xpa deficiency reduces CAG trinucleotide repeat instability in neuronal tissues in a mouse model of SCA1. Human molecular genetics. 2011;20(24):4822–30. Epub 2011/09/20. doi: 10.1093/hmg/ddr421 21926083

35. Kovtun IV, Johnson KO, McMurray CT. Cockayne syndrome B protein antagonizes OGG1 in modulating CAG repeat length in vivo. Aging. 2011;3(5):509–14. Epub 2011/05/14. 21566259

36. Xun Z, Rivera-Sanchez S, Ayala-Pena S, Lim J, Budworth H, Skoda EM, et al. Targeting of XJB-5-131 to Mitochondria Suppresses Oxidative DNA Damage and Motor Decline in a Mouse Model of Huntington's Disease. Cell reports. 2012. Epub 2012/11/06.

37. Johri A, Calingasan NY, Hennessey TM, Sharma A, Yang L, Wille E, et al. Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington's disease. Human molecular genetics. 2012;21(5):1124–37. Epub 2011/11/19. doi: 10.1093/hmg/ddr541 22095692

38. Manley K, Shirley TL, Flaherty L, Messer A. Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice. Nat Genet. 1999;23(4):471–3. Epub 1999/12/02. 10581038

39. van den Broek WJ, Nelen MR, Wansink DG, Coerwinkel MM, te Riele H, Groenen PJ, et al. Somatic expansion behaviour of the (CTG)n repeat in myotonic dystrophy knock-in mice is differentially affected by Msh3 and Msh6 mismatch-repair proteins. Human molecular genetics. 2002;11(2):191–8. Epub 2002/01/26. 11809728

40. Savouret C, Brisson E, Essers J, Kanaar R, Pastink A, te Riele H, et al. CTG repeat instability and size variation timing in DNA repair-deficient mice. Embo J. 2003;22(9):2264–73. Epub 2003/05/03. 12727892

41. Kovtun IV, Spiro C, McMurray CT. Triplet repeats and DNA repair: germ cell and somatic cell instability in transgenic mice. Methods in molecular biology. 2004;277 : 309–19. Epub 2004/06/18. 15201465

42. Owen BA, Yang Z, Lai M, Gajec M, Badger JD 2nd, Hayes JJ, et al. (CAG)(n)-hairpin DNA binds to Msh2-Msh3 and changes properties of mismatch recognition. Nature structural & molecular biology. 2005;12(8):663–70. Epub 2005/07/19.

43. Wheeler VC, Lebel LA, Vrbanac V, Teed A, te Riele H, MacDonald ME. Mismatch repair gene Msh2 modifies the timing of early disease in Hdh(Q111) striatum. Human molecular genetics. 2003;12(3):273–81. Epub 2003/01/30. 12554681

44. Dragileva E, Hendricks A, Teed A, Gillis T, Lopez ET, Friedberg EC, et al. Intergenerational and striatal CAG repeat instability in Huntington's disease knock-in mice involve different DNA repair genes. Neurobiology of disease. 2009;33(1):37–47. Epub 2008/10/22. doi: 10.1016/j.nbd.2008.09.014 18930147

45. Kovalenko M, Dragileva E, St Claire J, Gillis T, Guide JR, New J, et al. Msh2 acts in medium-spiny striatal neurons as an enhancer of CAG instability and mutant huntingtin phenotypes in Huntington's disease knock-in mice. PLoS One. 2012;7(9):e44273. Epub 2012/09/13. doi: 10.1371/journal.pone.0044273 22970194

46. de Wind N, Dekker M, Berns A, Radman M, te Riele H. Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. Cell. 1995;82(2):321–30. Epub 1995/07/28. 7628020

47. Goellner GM, Tester D, Thibodeau S, Almqvist E, Goldberg YP, Hayden MR, et al. Different mechanisms underlie DNA instability in Huntington disease and colorectal cancer. Am J Hum Genet. 1997;60(4):879–90. Epub 1997/04/01. 9106534

48. Bak ST, Sakellariou D, Pena-Diaz J. The dual nature of mismatch repair as antimutator and mutator: for better or for worse. Frontiers in genetics. 2014;5 : 287. Epub 2014/09/06. doi: 10.3389/fgene.2014.00287 25191341

49. Trushina E, Du Charme J, Parisi J, McMurray CT. Neurological abnormalities in caveolin-1 knock out mice. Behav Brain Res. 2006;172(1):24–32. Epub 2006/06/06. 16750274

50. Trushina E, Canaria CA, Lee DY, McMurray CT. Loss of caveolin-1 expression in knock-in mouse model of Huntington's disease suppresses pathophysiology in vivo. Human molecular genetics. 2014;23(1):129–44. Epub 2013/09/12. doi: 10.1093/hmg/ddt406 24021477

51. Wipf P, Xiao J, Jiang J, Belikova NA, Tyurin VA, Fink MP, et al. Mitochondrial targeting of selective electron scavengers: synthesis and biological analysis of hemigramicidin-TEMPO conjugates. J Am Chem Soc. 2005;127(36):12460–1. Epub 2005/09/08. 16144372