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Vol. 100, No. 1-4, 2003
Issue release date: 2003
Cytogenet Genome Res 100:175–183 (2003)

Molecular genetics of spinocerebellar ataxia type 8 (SCA8)

Mosemiller A.K. · Dalton J.C. · Day J.W. · Ranum L.P.W.
Departments of aGenetics, Cell Biology, and Development, bNeurology, and the cInstitute of Human Genetics, University of Minnesota, Minneapolis MN (USA)

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We previously reported that a transcribed but untranslated CTG expansion causes a novel form of ataxia, spinocerebellar ataxia type 8 (SCA8) (Koob et al., 1999). SCA8 was the first example of a dominant spinocerebellar ataxia that is not caused by the expansion of a CAG repeat translated into a polyglutamine tract. This slowly progressive form of ataxia is characterized by dramatic repeat instability and a high degree of reduced penetrance. The clinical and genetic features of the disease are discussed below.    

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  1. Alwazzan M, Newman E, Hamshere MG, Brook JD: Myotonic dystrophy is associated with a reduced level of RNA from the DMWD allele adjacent to the expanded repeat. Hum molec Genet 8:1491–1497 (1999).
  2. Anderson JH, Yavuz MC, Kazar BM, Christova P, Gomez CM: The vestibular-ocular reflex and velocity storage in spinocerebellar ataxia 8. Arch Ital Biol 140:323–329 (2002).
  3. Benzow KA, Koob MD: The KLHL1-antisense transcript (KLHL1AS) is evolutionarily conserved. Mammal Genome 13:134–141 (2002).
  4. Boucher CA, King SK, Carey N, Krahe R, Winchester CL, Rahman S, Creavin T, Meghji P, Bailey MES, Chartier FL, Brown SD, Siciliano MJ, Johnson KJ: A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat. Hum molec Genet 4:1919–1925 (1995).
  5. Brook JD, McCurrah ME, Harley HG, Buckler AJ, Church D, Aburatani H, Hunter K, Stanton VP, Thirion J-P, Hudson T, Sohn R, Zemelman B, Snell RG, Rundle SA, Crow S, Davies J, Shelbourne P, Buxton J, Jones C, Juvonen V, Johnson K, Harper PS, Shaw DJ, Housman DE: Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell 68:799–808 (1992).
  6. Brusco A, Cagnoli C, Franco A, Dragone E, Nardacchione A, Grosso E, Mortara P, Mutani R, Migone N, Orsi L: Analysis of SCA8 and SCA12 loci in 134 Italian ataxic patients negative for SCA1-3, 6, and 7 CAG expansions. J Neurol 249:923–929 (2002).
  7. Cancel G, Durr A, Didierjean O, Imbert G, Burk K, Lezin A, Belal S, Benomar A, Abadabendib M, Vial C, Guimaraes J, Chneiweiss H, Stevanin G, Yvert G, Abbas N, Saudou F, Lebre A, Yahyaoui M, Hentati F, Vernant J, Klockgether T, Mandel J, Agrid Y, Brice A: Molecular and clinical correlations in spinocerebellar ataxia 2 – a study of 32 families. Hum molec Genet 6:709–715 (1997).
  8. Cellini E, Nacmias B, Forleo P, Piacentini S, Guarnieri BM, Serio A, Calabro A, Renzi D, Sorbi S: Genetic and clinical analysis of spinocerebellar ataxia type 8 repeat expansion in Italy. Arch Neurol 58:1856–1859 (2001).
  9. Charlet BN, Savkur RS, Singh G, Philips AV, Grice EA, Cooper TA: Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing. Mol Cell 10:45–53 (2002).
  10. Chung M-Y, Ranum LPW, Duvick LA, Servadio A, Zoghbi HY, Orr HT: Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type 1. Nature Genet 5:254–258 (1993).
  11. David G, Abbas N, Stevanin G, Durr A, Yvert G, Cancel G, Weber C, Imbert G, Saudou F, Antoniou E, Drabkin H, Gemmill R, Giunti P, Benomar A, Wood NW, Ruberg M, Agid Y, Mandel J, Brice A: Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nature Genet 17:65–70 (1997).
  12. Davis BM, McCurrach ME, Taneja KL, Singer RH, Housman DE: Expansion of a CUG trinucleotide repeat in the 3′ untranslated region of myotonic dystrophy protein kinase transcripts results in nuclear retention of transcripts. Proc natl Acad Sci, USA 94:7388–7393 (1997).
  13. Day JW, Roelofs R, Leroy B, Pech I, Benzow K, Ranum LPW: Clinical and genetic characteristics of a five-generation family with a novel form of myotonic dystrophy (DM2). Neuromuscul Disord 9:19–27 (1999).
  14. Day JW, Schut LJ, Moseley ML, Durand AC, Ranum LPW: Spinocerebellar ataxia type 8: clinical features in a large family. Neurology 55:649–657 (2000).
  15. Day JW, Ricker K, Jacobsen JF, Rasmussen LJ, Dick KA, Kress W, Schneider C, Koch MC, Beilman GJ, Harrison AR, Dalton JC, Ranum LPW: Myotonic dystrophy type 2: molecular, diagnostic and clinical spectrum. Neurology 60:657–664 (2003).
  16. Fardaei M, Rogers MT, Thorpe HM, Larkin K, Hamshere MG, Harper PS, Brook JD: Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells. Hum molec Genet 11:805–814 (2002).

    External Resources

  17. Fu Y-H, Pizzuti A, Fenwick RGJ, King J, Rajnarayan S, Dunne PW, Dubel J, Nasser GA, Ashizawa T, De Jong P, Wieringa B, Korneluk R, Perryman MB, Epstein HF, Caskey CT: An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255:1256–1258 (1992).
  18. Fu Y-H, Friedman DL, Richards S, Pearlman JA, Gibbs RA, Pizzuti A, Ashizawa T, Perryman MB, Scarlato G, Fenwick RG, Caskey CT: Decreased expression of myotonin-protein kinase messenger RNA and protein in adult form of myotonic dystrophy. Science 260:235–238 (1993).
  19. Groenen P, Wieringa B: Expanding complexity in myotonic dystrophy. Bioessays 20:901–912 (1998).
  20. Harper PS: Myotonic Dystrophy. 3rd ed (W.B. Saunders, London, 2001).
  21. Ikeda Y, Shizuka M, Watanabe M, Okamoto K, Shoji M: Molecular and clinical analyses of spinocerebellar ataxia type 8 in Japan. Neurology 54:950–955 (2000a).
  22. Ikeda Y, Shizuka-Ikeda M, Watanabe M, Schmitt M, Okamoto K, Shoji M: Asymptomatic CTG expansion at the SCA8 locus is associated with cerebellar atrophy on MRI. J Neurol Sci 182:76–79 (2000b).
  23. Jansen G, Groenen PJTA, Bachner D, Jap PHK, Coerwinkel M, Oerlemans F, van den Broek W, Gohlsch B, Pette D, Plomp JJ, Molenaar PC, Nederhof MGJ, van Echted CJA, Dekker M, Berns A, Hameister H, Wieringa B: Abnormal myotonic dystrophy protein kinase levels produce only mild myopathy in mice. Nature Genet 13:316–324 (1996).
  24. Janzen MA, Moseley ML, Benzow KA, Day JW, Koob MD, Ranum LPW: Limited expression of SCA8 is consistent with cerebellar pathogenesis and toxic gain of function RNA model. Am J hum Genet 65(Supplement):A267 (1999).
  25. Jin P, Warren ST: Understanding the molecular basis of fragile X syndrome. Hum molec Genet 9:901–908 (2000).
  26. Jodice C, Mantuano E, Veneziano L, Trettel F, Sabbadini G, Calandriello L, Francia A, Spadaro M, Pierelli F, Salvi F, Ophoff R, Frants R, Frontali M: Episodic ataxia type 2 (EA2) and spinocerebellar atxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p. Hum molec Genet 6:1973–1978 (1997).
  27. Juvonen V, Hietala M, Paivarinta M, Rantamaki M, Hakamies L, Kaakkola S, Vierimaa O, Penttinen M, Savontaus ML: Clinical and genetic findings in Finnish ataxia patients with spinocerebellar ataxia 8 repeat expansion. Ann Neurol 48:354–361 (2000).
  28. Klesert TR, Otten AD, Bird TD, Tapscott SJ: Trinucleotide repeat expansion at the myotonic dystrophy locus reduces expression of DMAHP. Nature Genet 16:402–406 (1997).
  29. Koob MD, Benzow KA, Bird TD, Day JW, Moseley ML, Ranum LPW: Rapid cloning of expanded trinucleotide repeat sequences from genomic DNA. Nature Genet 18:72–75 (1998).
  30. Koob MD, Moseley ML, Schut LJ, Benzow KA, Bird TD, Day JW, Ranum LPW: An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nature Genet 21:379–384 (1999).
  31. Liquori C, Ricker K, Moseley ML, Jacobsen JF, Kress W, Naylor S, Day JW, Ranum LPW: Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293:864–867 (2001).
  32. Lu X, Timchenko NA, Timchenko LT: Cardiac elav-type RNA-binding protein (ETR-3) binds to RNA CUG repeats expanded in myotonic dystrophy. Hum molec Genet 8:53–60 (1999).
  33. Maciel P, Gaspar C, DeStefano AL, Silveira I, Coutinho P, Radvany J, Dawson DM, Sudarsky L, Guimaraes J, Loureiro JEL, Nezarati MM, Corwin LI, Lopes-Cendes I, Rooke K, Rosenburg R, MacLeod D, Farrer LA, Sequeiros J, Roulean GA: Correlation between CAG repeat length and clinical features in Machado-Joseph disease. Am J hum Genet 57:54–61 (1995).
  34. Mahadevan M, Tsilfidis C, Sabourin L, Shutler G, Amemiya C, Jansen G, Neville C, Narang M, Barcelo J, O’Hoy K, Leblond S, Earle-MacDonald J, De Jong PJ, Wieringa B, Koneluk RG: Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science 255:1253–1255 (1992).
  35. Mankodi A, Logigian E, Callahan L, McClain C, White R, Henderson D, Krym M, Thornton CA: Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat. Science 289:1769–1773 (2000).
  36. Mankodi A, Takahashi MP, Jiang H, Beck CL, Bowers WJ, Moxley RT, Cannon SC, Thornton CA: Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol Cell 10:35–44 (2002).
  37. Maruyama H, Nakamura S, Matsuyama Z, Sakai T, Doyu M, Sobue G, Seto M, Tsujihata M, Oh-i T, Nishio T, Sunohara N, Takahashi R, Hayashi M, Nishino I, Ohtake T, Oda T, Nishimura M, Saida T, Matsumoto H, Baba M, Kawaguchi Y, Kakizuka A, Kawakimi H: Molecular features of the CAG repeats and clinical manifestation of Machado-Joseph disease. Hum molec Genet 4:807–812 (1995).
  38. Miller JW, Urbinati CR, Teng-Umnuay P, Stenberg MG, Byrne BJ, Thornton CA, Swanson MS: Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J 19:4439–4448 (2000).
  39. Moseley ML, Benzow KA, Schut LJ, Bird TD, Gomez CM, Barkhaus PE, Blindauer KA, Labuda M, Pandolfo M, Koob MD, Ranum LPW: Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families. Neurology 51:1666–1671 (1998).
  40. Moseley ML, Jacobsen JF, Liquori C, Durand A, Davis L, Ikeda Y, Bird TD, Spiegel R, Ashizawa T, Pandolfo M, Potter N, Schaefer A, Milunsky J, Kennedy JL, Seltzer WK, Atwood L, Vincent JB, Day JW, Ranum LPW: SCA8 CTG expansion: evidence for a common haplotype and highly mutable region on both ataxia and non-ataxia chromosomes. Am J hum Genet 67(Supplement):362 (2000a).
  41. Moseley ML, Schut LJ, Bird TD, Day JW, Ranum LPW: Reply to Stevanin et al. and Worth et al. Nature Genet 24:215 (2000b).
  42. Moseley ML, Schut LJ, Bird TD, Koob MD, Day JW, Ranum LPW: SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance. Hum molec Genet 9:2125–2130 (2000c).
  43. Moseley ML, Weatherspoon M, Rasmussen L, Day JW, Ranum LPW: SCA8 BAC transgenic mice have a progressive and lethal neurological phenotype demonstrating pathogenicity of the CTG expansion. Am J hum Genet 71 (Supplement):178 (2002).
  44. Mutsuddi M, Benzow K, Littleton JT, Koob MD, Rebay I: Using a Drosophila model to characterize spinocerebellar ataxia 8 (SCA8) induced neurodegeneration, Abstract Viewer/Itinerary Planner, Program No. 417.411. (Society for Neuroscience, Washington DC 2002).
  45. Nemes JP, Benzow KA, Moseley ML, Ranum LPW, Koob MD: The SCA8 transcript is an antisense RNA to a brain-specific transcript encoding a novel actin-binding protein (KLHL1). Hum molec Genet 9:1543–1551 (Correction/Addition Hum molec Genet 9:2777) (2000).
  46. Otten AD, Tapscott SJ: Triplet repeat expansion in myotonic dystrophy alters the adjacent chromatin structure. Proc natl Acad Sci, USA 92:5465–5469 (1995).
  47. Philips AV, Timchenko LT, Cooper TA: Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science 280:737–741 (1998).
  48. Ranum LPW, Day JW: Dominantly inherited non-coding microsatellite expansion disorders. Curr Opin Genet Dev 12:266–271 (2002a).
  49. Ranum LPW, Day JW: Myotonic dystrophy: Clinical and molecular parallels between DM1 and DM2. Curr Neurol Neurosci Rep 2:465–470 (2002b).
  50. Ranum LPW, Rasmussen PF, Benzow KA, Koob MD, Day JW: Genetic mapping of a second myotonic dystrophy locus. Nature Genet 19:196–198 (1998).
  51. Ranum LPW, Moseley ML, Leppert M, Guan den Eng MF, La Spada AR, Koob MD, Day JD: Massive CTG expansions and deletions reduce penetrance of spinocerebellar ataxia type 8. Am J hum Genet 65(Supplement):A466 (1999).
  52. Ranum LPW, Liquori C, Moseley ML, Jacobsen JF, Philips AV, Savkur RS, Kress W, Naylor S, Cooper TA, Ricker K, Day JW: Myotonic dystrophy type 2 is caused by a CCTG expansion in intron 1 of ZNF9. Am J hum Genet 69(Supplement):A211 (2001).
  53. Ranum LPW, Moseley ML, Jacobsen JF, Liquori C, Ikeda Y, Bird TD, Ashizawa T, Seltzer WK, Vincent JB, Day JW: The SCA8 CTG expansion causes ataxia: evidence from haplotype analysis. Neurology 58:A310–A311 (2002).
  54. Robinson DN, Cooley L: Drosophila kelch is an oligomeric ring canal actin organizer. J Cell Biol 138:799–810 (1997).
  55. Savkur RS, Philips AV, Cooper TA: Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nature Genet 29:40–47 (2001).
  56. Seznec H, Agbulut O, Sergeant N, Savouret C, Ghestem A, Tabti N, Willer JC, Ourth L, Duros C, Brisson E, Fouquet C, Butler-Browne G, Delacourte A, Junien C, Gourdon G: Mice transgenic for the human myotonic dystrophy region with expanded CTG repeats display muscular and brain abnormalities. Hum molec Genet 10:2717–2726 (2001).

    External Resources

  57. Silveira I, Alonso I, Guimaraes L, Mendonca P, Santos C, Maciel P, Figdalgo de Matos JM, Costa M, Barbot C, Tuna A, Barros J, Jardim LB, Coutinho P, Sequeiros J: High germinal instability of the (CTG)n at the SCA8 locus of both expanded and normal alleles. Am J hum Genet 66:830–840 (2000).
  58. Sobrido M-J, Cholfin JA, Perlman S, Pulst SM, Geschwind DH: SCA8 repeats expansions in ataxia: a controversial association. Neurology 57:1310–1312 (2001).
  59. Stevanin G, Herman A, Durr A, Jodice C, Frontali M, Agid Y, Brice A: Are (CTG)n expansions at the SCA8 locus rare polymorphisms? Nature Genet 24:213 (2000).
  60. Taneja KL, McCurrach M, Schalling M, Housman D, Singer RH: Foci of trinucleotide repeat transcripts in nuclei of myotonic dystrophy cells and tissues. J Cell Biol 128:995–1002 (1995).
  61. Tapscott SJ: Deconstructing myotonic dystrophy. Science 289:1701–1702 (2000).
  62. Thornton CA, Wymer JP, Simmons Z, McClain C, Moxley RT: Expansion of the myotonic dystrophy CTG repeat reduces expression of the flanking DMAHP gene. Nature Genet 16:407–409 (1997).
  63. Timchenko LT, Miller JW, Timchenko NA, DeVore DR, Datar KV, Lin L, Roberts R, Caskey CT, Swanson MS: Identification of a (CUG)n triplet repeat RNA-binding protein and its expression in myotonic dystrophy. Nucl Acids Res 24:4407–4414 (1996).
  64. Topisirovic I, Dragasevic N, Savic D, Ristic A, Keckarevic M, Keckarevic D, Culjkovic B, Petrovic I, Romac S, Kostic VS: Genetic and clinical analysis of spinocerebellar ataxia type 8 repeat expansion in Yugoslavia. Clin Genet 62:321–324 (2002).
  65. Tsilfidis C, MacKenzie AE, Mettler G, Barcelo J, Korneluk RG: Correlation between CTG trinucleotide repeat length and frequency of severe congenital myotonic dystrophy. Nature Genet 1:192–195 (1992).
  66. Vincent JB, Yuan QP, Schalling M, Adolfsson R, Azevedo MH, Macedo A, Bauer A, DallaTorre C, Medeiros HM, Pato MT, Pato CN, Bowen T, Guy CA, Owen MJ, O’Donovan MC, Paterson AD, Petronis A, Kennedy JL: Long repeat tracts at SCA8 in major psychosis. Am J med Genet 96:873–876 (2000).
  67. Worth PF, Houlden H, Giunti P, Davis MB, Wood NW: Large, expanded repeats in SCA8 are not confined to patients with cerebellar ataxia. Nature Genet 24:214–215 (2000).
  68. Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, Dobyns WB, Subramony SH, Zoghbi HY, Lee CC: Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha-1A-voltage-dependent calcium channel. Nature Genet 15:62–69 (1997).

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