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Vol. 100, No. 1-4, 2003
Issue release date: 2003

Why is SCA12 different from other SCAs?

Holmes S.E. · O’Hearn E. · Margolis R.L.

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Spinocerebellar ataxia type 12 (SCA12), now described in European-American and Asian (Indian) pedigrees, is unique among the SCAs from clinical, pathological, and molecular perspectives. Clinically, the distinguishing feature is early and prominent action tremor with variability in other signs. Pathologically, brain MRIs also suggest variability, with promi- nent cortical as well as cerebellar atrophy. Genetically, SCA12 is caused by a CAG repeat expansion that does not encode polyglutamine; we speculate that the mutation may affect expression of the gene PPP2R2B, which encodes a brain-specific regulatory subunit of the protein phosphatase PP2A.   

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  1. 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).
  2. Burge C, Karlin S: Prediction of complete gene structures in human genomic DNA. J molec Biol 268:78–94 (1997).

    External Resources

  3. Cholfin JA, Sobrido MJ, Perlman S, Pulst SM, Geschwind DH: The SCA12 mutation as a rare cause of spinocerebellar ataxia. Arch Neurol 58:1833–1835 (2001).
  4. Ferrigno P, Langan TA, Cohen P: Protein phosphatase 2A1 is the major enzyme in vertebrate cell extracts that dephosphorylates several physiological substrates for cyclin-dependent protein kinases. Mol Biol Cell 4:669–677 (1993).
  5. Fu Y-H, Kuhl DPA, Pizzuti A, Pieretti M, Sutcliffe JS, Richards S, Verkerk AJMH, Holden JJA, Fenmwick RG, Warren ST, Nelson DL, Caskey CT: Variation of the CGG repeat at the Fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67:1047–1058 (1991).
  6. Fujigasaki H, Verma IC, Camuzat A, Margolis RL, Zander C, Lebre AS, Jamot L, Saxena R, Anand I, Holmes SE, Ross CA, Durr A, Brice A: SCA12 is a rare locus for autosomal dominant cerebellar ataxia: a study of an Indian family. Ann Neurol 49:117–121 (2001).
  7. Grewal RP, Tayag E, Figueroa KP, Zu L, Durazo A, Nunez C, Pulst SM: Clinical and genetic analysis of a distinct autosomal dominant spinocerebellar ataxia. Neurol 51:1423–1426 (1998).
  8. Healy AM, Zolnierowicz S, Stapleton AE, Goebl M, DePaoli-Roach AA, Pringle JR: CDC55 a Saccharomyces cerevisiae gene involved in cellular morphogenesis: identification characterization and homology to the B subunit of mammalian type 2A protein phosphatase. Mol Cell Biol 11:5767–5780 (1991).
  9. Holmes SE, O’Hearn EE, McInnis MG, Gorelick-Feldman DA, Kleiderlein JJ, Callahan C, Kwak NG, Ingersoll-Ashworth RG, Sherr M, Sumner AJ, Sharp AH, Ananth U, Seltzer WK, Boss MA, Vieria-Saecker AM, Epplen JT, Riess O, Ross CA, Margolis RL: Expansion of a novel CAG trinucleotide repeat in the 5′ region of PPP2R2B is associated with SCA12. Nature Genet 23:391–392 (1999).
  10. Holmes SE, Fujigasaki H, O’Hearn E, Antonarakis S, Cooper JK, Callahan C, Hwang J, Gorelick-Feldman D, Verma IC, Saxena R, Durr A, Brice A, Ross CA, Margolis RL: Spinocerebellar ataxia type 12 (SCA12): additional evidence for a causative role of the CAG repeat expansion in PPP2R2B. abstract Am J hum Genet 67:1074 (2000).
  11. Holmes SE, O’Hearn E, Ross CA, Margolis RL: SCA12: an unusual mutation leads to an unusual spinocerebellar ataxia. Brain Res Bull 56:397–403 (2001).
  12. Holmes SE, Hwang H, O’Hearn E, Antonarakis SE, Chip S, Strck S, Ross CA, Margolis RL: Genomic structure and splice variants of PPP2R2B the gene associated with spinocerebellar ataxia type 12 (SCA12). Abstract Am J hum Genet 71:973 (2002).
  13. Holmes SE, O’Hearn E, Brahmachari SK, Choudhry S, Srivastava AK, Jain S, Ross CA, Margolis RL: SCA12, in Pulst SM (ed): Genetics of Movement Disorders, pp 121–132 (Academic Press, San Diego 2003).
  14. Hrimech M, Yao XJ, Branton PE, Cohen EA: Human immunodeficiency virus type 1 Vpr-mediated G(2) cell cycle arrest: Vpr interferes with cell cycle signaling cascades by interacting with the B subunit of serine/threonine protein phosphatase 2A. EMBO J 19:3956–3967 (2000).
  15. Ince TA, Scotto KW: A conserved downstream element defines a new class of RNA polymerase II promoters. J biol Chem 270:30249–30252 (1995).
  16. 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).
  17. Lalioti MD, Scott HS, Antonarakis SE: Altered spacing of promoter elements due to the dodecamer repeat expansion contributes to reduced expression of the cystatin B gene in EPM1. Hum molec Genet 8:1791–1798 (1999).
  18. Liquori CL, Ricker K, Moseley ML, Jacobsen JF, Kress W, Naylor SL, Day JW, Ranum LPW: Myotonic Dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293:864–867 (2001).
  19. Lubert EJ, Hong YI, Sarge KD: Interaction between protein phosphatase 5 and the A subunit of protein phosphatase 2A: Evidence for a heterotrimeric form of protein phosphatase 5. J biol Chem 276:38582–38587 (2001).
  20. 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 289:1701–1702 (2000).
  21. Margolis RL: The spinocerebellar ataxias: Order emerges from chaos. Curr Neurol Neurosc Rep 2:447-456 (2002).
  22. Maruyama H, Izumi Y, Morino H, Oda M, Toji H, Nakamura S, Kawakami H: Difference in disease-free survival curve and regional distribution according to subtype of spinocerebellar ataxia: A study of 1286 Japanese patients. Am J med Genet 114:578–583 (2002).
  23. Matsuura T, Yamagata T, Burgess DL, Rasmussen A, Grewal RP, Watase K, Khajavi M, McCall AE, Davis CF, Zu L, Achari M, Pulst SM, Alonso E, Noebels JL, Nelson DL, Zoghbi HY, Ashizawa T: Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nature Genet 26:191–194 (2000).
  24. Mayer RE, Hendrix P, Cron P, Mattheis R, Stone SR, Goris J, Merlevede W, Hofsteenge J, Hemmings BA: Structure of the 55-kDa regulatory subunit of protein phosphatase 2A: evidence for a neuronal-specific isoforms. Biochem 30:3589–3597 (1991).
  25. Mayer-Jaekel RE, Ohkura H, Gomes R, Sunkel CE, Baumgartner S, Hemmings BA, Glover DM: The 55 kDa regulatory subunit of Drosophila protein phosphatase 2A is required for anaphase. Cell 72:621–633 (1993).
  26. Mayer-Jaekel RE, Ohkura H, Ferrigno P, Andjelkovic N, Shiomi K, Uemura T, Glover DM, Hemmings BA: Drosophila mutants in the 55 kDa regulatory subunit of protein phosphatase 2A show strongly reduced ability to dephosphorylate substrates of p34cdc2. J Cell Sci 107:2609–2616 (1994).
  27. McCright B, Rivers AM, Audlin S, Virshup DM: The B56 family of protein phosphatase 2A (PP2A) regulatory subunits encodes differentiation-induced phosphoproteins that target PP2A to both nucleus and cytoplasm. J biol Chem 271:22081–22089 (1996).
  28. Millward TA, Zolnierowicz S, Hemmings BA: Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci 24:186–191 (1999).
  29. Moseley ML, Benzow KA, Schut LJ, Bird TD, Gomez CM, Barkhaus PE, Blindauer KA, Labuda M, Pandolfo M, Koob MD, Ranum LP: Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families. Neurol 51:1666–1671 (1998).
  30. Nemes JP, Benzow KA, Moseley ML, et al: The SCA8transcript is an antisense RNA to a brain-specific transcript encoding a novelactin-binding protein (KLHL1). Hum molec Genet 9:1543–1551 (2000).
  31. O’Hearn E, Holmes SE Calvert PC, Ross CA, Margolis RL: SCA12: Tremor with cerebellar and cortical atrophy is associated with a CAG repeat expansion. Neurol 56:299–303 (2001).
  32. Patel PI, Isaya G: Friedreich ataxia: from GAA triplet-repeat expansion to frataxin deficiency. Am J hum Genet 69:15–24 (2001).
  33. Price NE, Mumby MC: Brain protein serine/threonine phosphatases. Curr Opin Neurobiol 9:336–342 (1999).
  34. Santoro MF, Annand RR, Robertson MM, Peng Y-W, Brady MJ, Mankovich JA, Hackett MC, Ghayur T, Walter G, Wong WW, Giegel DA: Regulation of protein phosphatase 2A activity by caspase-3 during apoptosis. J biol Chem 273:13119–13128 (1998).
  35. Schols L, Szymanski S, Peters S, Przuntek H, Epplen JT, Hardt C, Riess O: Genetic background of apparently idiopathic sporadic cerebellar ataxia. Hum Genet 107:132–137 (2000).
  36. Shenolikar S: Protein serine/threonine phosphatases – new avenues for cell regulation. A Rev Cell Biol 10:55–86 (1994).
  37. Shiomi K, Takeichi M, Nishida Y, Nishi Y, Uemura T: Alternative cell fate choice induced by low-level expression of a regulator of protein phosphatase 2A in the Drosophila peripheral nervous system. Devel 120:1591–1599 (1994).
  38. Silveira I, Miranda C, Guimarães L, Moreira M-C, Alonso I, Mendonça P, Ferro A, Pinto-Basto J, Coelho J, Ferreirinha F, Poirier J, Parreira E, Vale J, Januário C, Barbot C, Tuna A, Barros J, Koide R, Tsuji S, Holmes SE, Margolis RL, Jardim L, Pandolfo M, Coutinho P, Sequeiros J: Trinucleotide repeats in 202 families with ataxia: a small expanded (CAG)n allele at the SCA17 locus. Arch Neur 59:623–629 (2002).
  39. Sontag E, Nunbhakdi-Craig V, Lee G, Bloom GS, Mumby MC: Regulation of the phosphorylation state and microtubule-binding activity of Tau by protein phosphatase 2A. Neuron 17:1201–1207 (1996).
  40. Sontag E, Nunbhakdi-Craig V, Lee G, Brandt R, Kamibayashi C, Kuret J, et al: Molecular interactions among protein phosphatase 2A, tau and microtubules. Implications for the regulation of tau phosphorylation and the development of tauopathies. J biol Chem 274:25490–25498 (1999).
  41. Srivastava AK, Choudhry S, Gopinath MS, Roy S, Tripathi M, Brahmachari SK, Jain S: Molecular and clinical correlation in five Indian families with spinocerebellar ataxia 12. Ann Neur 50:796–800 (2001).
  42. Strack S, Zaucha JA, Ebner FF, Colbran RJ, Wadzinski BE: Brain protein phosphatase 2A: developmental regulation and distinct cellular and subcellular localization by B subunits. J Comp Neurol 392:515–527 (1998).
  43. Strack S, Ruediger R, Walter G, Dagda RK, Barwacz CA, Cribbs JT: Protein phosphatase 2A holoenzyme assembly: identification of contacts between B-family regulatory and scaffolding A subunits. J biol Chem 277:20750–20755 (2002).
  44. Tehrani MA, Mumby MC, Kamibayashi C: Identification of a novel protein phosphatase 2A regulatory subunit highly expressed in muscle. J biol Chem 271:5164–5170 (1996).
  45. Trottier Y, Lutz Y, Stevanin G, Imbert G, Devys D, Cancel G, Saudou F, Weber C, David G, Tora L, Agid Y, Brice A, Mandel J-L: Polyglutamine expansion as a pathological epitope in Huntington’s disease and four dominant cerebellar ataxias. Nature 378:403–406 (1995).
  46. Turowski P, Myles T, Hemmings BA, Fernandez A, Lamb NJ: Vimentin dephosphorylation by protein phosphatase 2A is modulated by the targeting subunit B55. Mol Biol Cell 10:1997–2015 (1999).
  47. Verkerk AJMH, Pieretti M, Sutcliffe JS, Fu Y-H, Kuhl DPA, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang F, Eussen BE, van Ommen G-JB, Blonden LAJ, Riggins GJ, Chastain JL, Kunst CB, Galjaard H, Caskey CT, Nelson DL, Oostra BA, Warren ST: Identification of a gene (FMR-1) containing CGG repeat coincident with a breakpoint cluster region exhibiting length variation in Fragile X syndrome. Cell 65:905–914 (1991).
  48. Virshup DM: Protein phosphatase 2A: a panoply of enzymes. Curr Opin Cell Biol 12:180–185 (2000).

    External Resources

  49. Wera S, Hemmings BA: Serine/threonine protein phosphatases. Biochem J 311:17–29 (1995).
  50. Worth PF, Wood NW: Spinocerebellar ataxia type 12 is rare in the United Kingdom. Neurol 56:419–420 (2001).
  51. Yu S, Pritchard M, Kremer E, Lynch M, Nancarrow J, Baker E, Holman K, Mulley JC, Warren ST, Schlessinger D, Sutherland GR, Richards RI: Fragile X genotype characterized by an unstable region of DNA. Science 252:1179–1181 (1991).
  52. Zoghbi HY, Orr HT: Glutamine repeats and neurodegeneration. Ann Rev Neurosci 23:217–247 (2000).

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