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Mol Med. 1995 May; 1(4): 374–383.
PMCID: PMC2230005

Normal and expanded Huntington's disease gene alleles produce distinguishable proteins due to translation across the CAG repeat.

Abstract

BACKGROUND: An expanded CAG trinucleotide repeat is the genetic trigger of neuronal degeneration in Huntington's disease (HD), but its mode of action has yet to be discovered. The sequence of the HD gene places the CAG repeat near the 5' end in a region where it may be translated as a variable polyglutamine segment in the protein product, huntingtin. MATERIALS AND METHODS: Antisera directed at amino acid stretches predicted by the DNA sequence upstream and downstream of the CAG repeat were used in Western blot and immunohistochemical analyses to examine huntingtin expression from the normal and the HD allele in lymphoblastoid cells and postmortem brain tissue. RESULTS: CAG repeat segments of both normal and expanded HD alleles are indeed translated, as part of a discrete approximately 350-kD protein that is found primarily in the cytosol. The difference in the length of the N-terminal polyglutamine segment is sufficient to distinguish normal and HD huntingtin in a Western blot assay. CONCLUSIONS: The HD mutation does not eliminate expression of the HD gene but instead produces an altered protein with an expanded polyglutamine stretch near the N terminus. Thus, HD pathogenesis is probably triggered by an effect at the level of huntingtin protein.

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Selected References

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  • Martin JB, Gusella JF. Huntington's disease. Pathogenesis and management. N Engl J Med. 1986 Nov 13;315(20):1267–1276. [PubMed]
  • Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP., Jr Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol. 1985 Nov;44(6):559–577. [PubMed]
  • Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA, Tanzi RE, Watkins PC, Ottina K, Wallace MR, Sakaguchi AY, et al. A polymorphic DNA marker genetically linked to Huntington's disease. Nature. 1983 Nov 17;306(5940):234–238. [PubMed]
  • Gusella JF, MacDonald ME, Ambrose CM, Duyao MP. Molecular genetics of Huntington's disease. Arch Neurol. 1993 Nov;50(11):1157–1163. [PubMed]
  • Ambrose CM, Duyao MP, Barnes G, Bates GP, Lin CS, Srinidhi J, Baxendale S, Hummerich H, Lehrach H, Altherr M, et al. Structure and expression of the Huntington's disease gene: evidence against simple inactivation due to an expanded CAG repeat. Somat Cell Mol Genet. 1994 Jan;20(1):27–38. [PubMed]
  • Strong TV, Tagle DA, Valdes JM, Elmer LW, Boehm K, Swaroop M, Kaatz KW, Collins FS, Albin RL. Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues. Nat Genet. 1993 Nov;5(3):259–265. [PubMed]
  • Li SH, Schilling G, Young WS, 3rd, Li XJ, Margolis RL, Stine OC, Wagster MV, Abbott MH, Franz ML, Ranen NG, et al. Huntington's disease gene (IT15) is widely expressed in human and rat tissues. Neuron. 1993 Nov;11(5):985–993. [PubMed]
  • MacDonald ME, Lin C, Srinidhi L, Bates G, Altherr M, Whaley WL, Lehrach H, Wasmuth J, Gusella JF. Complex patterns of linkage disequilibrium in the Huntington disease region. Am J Hum Genet. 1991 Oct;49(4):723–734. [PubMed]
  • MacDonald ME, Novelletto A, Lin C, Tagle D, Barnes G, Bates G, Taylor S, Allitto B, Altherr M, Myers R, et al. The Huntington's disease candidate region exhibits many different haplotypes. Nat Genet. 1992 May;1(2):99–103. [PubMed]
  • Anderson MA, Gusella JF. Use of cyclosporin A in establishing Epstein-Barr virus-transformed human lymphoblastoid cell lines. In Vitro. 1984 Nov;20(11):856–858. [PubMed]
  • Warner JP, Barron LH, Brock DJ. A new polymerase chain reaction (PCR) assay for the trinucleotide repeat that is unstable and expanded on Huntington's disease chromosomes. Mol Cell Probes. 1993 Jun;7(3):235–239. [PubMed]
  • Rubinsztein DC, Leggo J, Barton DE, Ferguson-Smith MA. Site of (CCG) polymorphism in the HD gene. Nat Genet. 1993 Nov;5(3):214–215. [PubMed]
  • Miner LL, Pandalai SP, Weisberg EP, Sell SL, Kovacs DM, Kaplan BB. Cold-induced alterations in the binding of adrenomedullary nuclear proteins to the promoter region of the tyrosine hydroxylase gene. J Neurosci Res. 1992 Sep;33(1):10–18. [PubMed]
  • Dignam JD. Preparation of extracts from higher eukaryotes. Methods Enzymol. 1990;182:194–203. [PubMed]
  • Wexler NS, Young AB, Tanzi RE, Travers H, Starosta-Rubinstein S, Penney JB, Snodgrass SR, Shoulson I, Gomez F, Ramos Arroyo MA, et al. Homozygotes for Huntington's disease. Nature. 1987 Mar 12;326(6109):194–197. [PubMed]
  • Myers RH, Leavitt J, Farrer LA, Jagadeesh J, McFarlane H, Mastromauro CA, Mark RJ, Gusella JF. Homozygote for Huntington disease. Am J Hum Genet. 1989 Oct;45(4):615–618. [PubMed]
  • Hu QJ, Bautista C, Edwards GM, Defeo-Jones D, Jones RE, Harlow E. Antibodies specific for the human retinoblastoma protein identify a family of related polypeptides. Mol Cell Biol. 1991 Nov;11(11):5792–5799. [PMC free article] [PubMed]
  • Marquardt B, Stabel S. Sequence of a rat cDNA encoding the ERK1-MAP kinase. Gene. 1992 Oct 21;120(2):297–299. [PubMed]
  • Mueckler MM, Pitot HC. Sequence of the precursor to rat ornithine aminotransferase deduced from a cDNA clone. J Biol Chem. 1985 Oct 25;260(24):12993–12997. [PubMed]
  • The I, Murthy AE, Hannigan GE, Jacoby LB, Menon AG, Gusella JF, Bernards A. Neurofibromatosis type 1 gene mutations in neuroblastoma. Nat Genet. 1993 Jan;3(1):62–66. [PubMed]
  • Golubić M, Roudebush M, Dobrowolski S, Wolfman A, Stacey DW. Catalytic properties, tissue and intracellular distribution of neurofibromin. Oncogene. 1992 Nov;7(11):2151–2159. [PubMed]
  • Hoogeveen AT, Willemsen R, Meyer N, de Rooij KE, Roos RA, van Ommen GJ, Galjaard H. Characterization and localization of the Huntington disease gene product. Hum Mol Genet. 1993 Dec;2(12):2069–2073. [PubMed]

Articles from Molecular Medicine are provided here courtesy of The Feinstein Institute for Medical Research at North Shore LIJ