nature.com

The molecular genetics of Huntington disease — a history - Nature Reviews Genetics

  • ️Bates, Gillian P.
  • ️Wed Aug 31 2005
  • Bates, G. P., Harper, P. S. & Jones, A. L. (eds) Huntington's Disease (Oxford Univ. Press, Oxford, 2002).

    Google Scholar 

  • Harper, P. S. Huntington's disease (W.B. Saunders, London, 1996).

    Google Scholar 

  • Huntington, G. On chorea. Med. Surg. Reporter 26, 320–321 (1872).

    Google Scholar 

  • Mendel, G. Versuche über Pflanzenhybriden. Proc. Nat. Hist. Soc. Brunn 4, 3–47 (1865) (in German).

    Google Scholar 

  • Punnett, R. C. Mendelian inheritance in man. Proc. R. Soc. Med. 1, 135–168 (1908).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hoffmann, J. Über Chorea chronica progressiva (Huntingtonsche Chorea, Chorea hereditaria). Virchows Arch. A 111, 513–548 (1888) (in German).

    Article  Google Scholar 

  • Ridley, R. M., Frith, C. D., Crow, T. J. & Conneally, P. M. Anticipation in Huntington's disease is inherited through the male line but may originate in the female. J. Med. Genet. 25, 589–595 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duyao, M. et al. Trinucleotide repeat length instability and age of onset in Huntington's disease. Nature Genet. 4, 387–392 (1993).

    Article  CAS  PubMed  Google Scholar 

  • Telenius, H. et al. Molecular analysis of juvenile Huntington disease: the major influence on (CAG)n repeat length is the sex of the affected parent. Hum. Mol. Genet. 2, 1535–1540 (1993).

    Article  CAS  PubMed  Google Scholar 

  • Wexler, A. Mapping Fate (Times Books, New York, 1995).

    Google Scholar 

  • Pericak-Vance, M. A. et al. Genetic linkage studies in Huntington disease. Cytogenet. Cell Genet. 22, 640–645 (1978).

    Article  CAS  PubMed  Google Scholar 

  • Kan, Y. W. & Dozy, A. M. Polymorphism of DNA sequence adjacent to human β-globin structural gene: relationship to sickle mutation. Proc. Natl Acad. Sci. USA 75, 5631–5635 (1978).

    Article  CAS  PubMed  Google Scholar 

  • Botstein, D., White, R. L., Skolnick, M. & Davis, R. W. Construction of a genetic linkage map in man using restriction fragment length polymorphisms. Am. J. Hum. Genet. 32, 314–331 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wexler, N. S. et al. Homozygotes for Huntington's disease. Nature 326, 194–197 (1987).

    Article  CAS  PubMed  Google Scholar 

  • Gusella, J. F. et al. A polymorphic DNA marker genetically linked to Huntington's disease. Nature 306, 234–238 (1983).

    Article  CAS  PubMed  Google Scholar 

  • Wexler, N. S. et al. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proc. Natl Acad. Sci. USA 101, 3498–503 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Gilliam, T. C. et al. Localization of the Huntington's disease gene to a small segment of chromosome 4 flanked by D4S10 and the telomere. Cell 50, 565–571 (1987).

    Article  CAS  PubMed  Google Scholar 

  • Conneally, P. M. et al. Huntington disease: no evidence for locus heterogeneity. Genomics 5, 304–308 (1989).

    Article  CAS  PubMed  Google Scholar 

  • MacDonald, M. E. et al. Recombination events suggest potential sites for the Huntington's disease gene. Neuron 3, 183–190 (1989).

    Article  CAS  PubMed  Google Scholar 

  • Bates, G. P. et al. A yeast artificial chromosome telomere clone spanning a possible location of the Huntington disease gene. Am. J. Hum. Genet. 46, 762–775 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Snell, R. G. et al. Linkage disequilibrium in Huntington's disease: an improved localisation for the gene. J. Med. Genet. 26, 673–675 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Theilmann, J. et al. Non-random association between alleles detected at D4S95 and D4S98 and the Huntington's disease gene. J. Med. Genet. 26, 676–681 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • MacDonald, M. E. et al. Complex patterns of linkage disequilibrium in the Huntington disease region. Am. J. Hum. Genet. 49, 723–734 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bates, G. P. et al. Defined physical limits of the Huntington disease gene candidate region. Am. J. Hum. Genet. 49, 7–16 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Buckler, A. J. et al. Exon amplification: a strategy to isolate mammalian genes based on RNA splicing. Proc. Natl Acad. Sci. USA 88, 4005–4009 (1991).

    Article  CAS  PubMed  Google Scholar 

  • The Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72, 971–983 (1993).

  • Verkerk, A. J. et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65, 905–914 (1991).

    Article  CAS  PubMed  Google Scholar 

  • La Spada, A. R., Wilson, E. M., Lubahn, D. B., Harding, A. E. & Fischbeck, K. H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77–79 (1991).

    Article  CAS  PubMed  Google Scholar 

  • Brook, J. D. et al. 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).

    Article  CAS  PubMed  Google Scholar 

  • Snell, R. G. et al. Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease. Nature Genet. 4, 393–397 (1993).

    Article  CAS  PubMed  Google Scholar 

  • Andrew, S. E. et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nature Genet. 4, 398–403 (1993).

    Article  CAS  PubMed  Google Scholar 

  • Rubinsztein, D. C. et al. Phenotypic characterization of individuals with 30–40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36–39 repeats. Am. J. Hum. Genet. 59, 16–22 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Myers, R. H., Marans, K. S. & MacDonald, M. E. in Genetic Instabilities and Hereditary Neurological Diseases (eds Wells, R. D. & Warren, S. T.) 301–323 (Academic Press, San Diego, 1998).

    Google Scholar 

  • Nance, M. A., Mathias-Hagen, V., Breningstall, G., Wick, M. J. & McGlennen, R. C. Analysis of a very large trinucleotide repeat in a patient with juvenile Huntington's disease. Neurology 52, 392–394 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Rubinsztein, D. C. et al. Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease. Proc. Natl Acad. Sci. USA 94, 3872–3876 (1997).

    Article  CAS  PubMed  Google Scholar 

  • MacDonald, M. E. et al. Evidence for the GluR6 gene associated with younger onset age of Huntington's disease. Neurology 53, 1330–1332 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Telenius, H. et al. Somatic mosaicism in sperm is associated with intergenerational (CAG)n changes in Huntington disease. Hum. Mol. Genet. 4, 189–195 (1995); erratum in Hum. Mol. Genet. 4, 974 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Ranen, N. G. et al. Anticipation and instability of IT-15 (CAG)n repeats in parent–offspring pairs with Huntington disease. Am. J. Hum. Genet. 57, 593–602 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Myers, R. H. et al. De novo expansion of a (CAG)n repeat in sporadic Huntington's disease. Nature Genet. 5, 168–173 (1993).

    Article  CAS  PubMed  Google Scholar 

  • Goldberg, Y. P. et al. Increased instability of intermediate alleles in families with sporadic Huntington disease compared to similar sized intermediate alleles in the general population. Hum. Mol. Genet. 4, 1911–1918 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Falush, D., Almqvist, E. W., Brinkmann, R. R., Iwasa, Y. & Hayden, M. R. Measurement of mutational flow implies both a high new-mutation rate for Huntington disease and substantial underascertainment of late-onset cases. Am. J. Hum. Genet. 68, 373–385 (2000).

    Article  PubMed Central  Google Scholar 

  • Telenius, H. et al. Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm. Nature Genet. 6, 409–414 (1994); erratum in Nature Genet. 7, 113 (1994).

    Article  CAS  PubMed  Google Scholar 

  • Kennedy, L. et al. Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. Hum. Mol. Genet. 12, 3359–3367 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Strong, T. V. et al. Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues. Nature Genet. 5, 259–265 (1993).

    Article  CAS  PubMed  Google Scholar 

  • Li, S. H. et al. Huntington's disease gene (IT15) is widely expressed in human and rat tissues. Neuron 11, 985–993 (1993).

    Article  CAS  PubMed  Google Scholar 

  • DiFiglia, M. et al. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 14, 1075–1081 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Gutekunst, C. A. et al. Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies. Proc. Natl Acad. Sci. USA 92, 8710–8714 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Bhide, P. G. et al. Expression of normal and mutant huntingtin in the developing brain. J. Neurosci. 16, 5523–5535 (1996).

    Article  CAS  PubMed  Google Scholar 

  • Duyao, M. P. et al. Inactivation of the mouse Huntington's disease gene homolog Hdh. Science 269, 407–410 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Nasir, J. et al. Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81, 811–823 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Zeitlin, S., Liu, J. P., Chapman, D. L., Papaioannou, V. E. & Efstratiadis, A. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nature Genet. 11, 155–163 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Andrade, M. A. & Bork, P. HEAT repeats in the Huntington's disease protein. Nature Genet. 11, 115–116 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Harjes, P. & Wanker, E. E. The hunt for huntingtin function: interaction partners tell many different stories. Trends Biochem. Sci. 28, 425–433 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Goehler, H. et al. A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease. Mol. Cell 15, 853–865 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Perutz, M. F., Johnson, T., Suzuki, M. & Finch, J. T. Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases. Proc. Natl Acad. Sci. USA 91, 5355–5358 (1994).

    Article  CAS  PubMed  Google Scholar 

  • Scherzinger, E. et al. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell 90, 549–558 (1997).

    Article  CAS  PubMed  Google Scholar 

  • Bates, G. Huntingtin aggregation and toxicity in Huntington's disease. Lancet 361, 1642–1644 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Mangiarini, L. et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87, 493–506 (1996).

    Article  CAS  PubMed  Google Scholar 

  • Davies, S. W. et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537–548 (1997).

    Article  CAS  PubMed  Google Scholar 

  • DiFiglia, M. et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990–1993 (1997).

    Article  CAS  PubMed  Google Scholar 

  • Cha, J. H. et al. Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human Huntington disease gene. Proc. Natl Acad. Sci. USA 95, 6480–6485 (1998).

    Article  CAS  PubMed  Google Scholar 

  • Bates, G. P. & Murphy, K. P. in Huntington's Disease (eds Bates, G. P., Harper, P. S. & Jones, A. L.) 387–426 (Oxford Univ. Press, Oxford, 2002).

    Google Scholar 

  • Hickey, M. A. & Chesselet, M. F. The use of transgenic and knock-in mice to study Huntington's disease. Cytogenet. Genome Res. 100, 276–286 (2003).

    Article  CAS  PubMed  Google Scholar 

  • von Horsten, S. et al. Transgenic rat model of Huntington's disease. Hum. Mol. Genet. 12, 617–624 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Strand, A. D. et al. Gene expression in Huntington's disease skeletal muscle: a potential biomarker. Hum. Mol. Genet. (2005).

  • Bjorkqvist, M. et al. The R6/2 transgenic mouse model of Huntington's disease develops diabetes due to deficient β-cell mass and exocytosis. Hum. Mol. Genet. 14, 565–574 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto, A., Lucas, J. J. & Hen, R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell 101, 57–66 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Krobitsch, S. & Lindquist, S. Aggregation of huntingtin in yeast varies with the length of the polyglutamine expansion and the expression of chaperone proteins. Proc. Natl Acad. Sci. USA 97, 1589–1594 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Trettel, F. et al. Dominant phenotypes produced by the HD mutation in STHdhQ111 striatal cells. Hum. Mol. Genet. 9, 2799–2809 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Apostol, B. L. et al. A cell-based assay for aggregation inhibitors as therapeutics of polyglutamine-repeat disease and validation in Drosophila. Proc. Natl Acad. Sci. USA 100, 5950–5955 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Faber, P. W., Alter, J. R., MacDonald, M. E. & Hart, A. C. Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proc. Natl Acad. Sci. USA 96, 179–184 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Satyal, S. H. et al. Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 97, 5750–5755 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Parker, J. A. et al. Expanded polyglutamines in Caenorhabditis elegans cause axonal abnormalities and severe dysfunction of PLM mechanosensory neurons without cell death. Proc. Natl Acad. Sci. USA 98, 13318–13323 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Jackson, G. R. et al. Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron 21, 633–642 (1998).

    Article  CAS  PubMed  Google Scholar 

  • Marsh, J. L. et al. Expanded polyglutamine peptides alone are intrinsically cytotoxic and cause neurodegeneration in Drosophila. Hum. Mol. Genet. 9, 13–25 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Kazemi-Esfarjani, P. & Benzer, S. Genetic suppression of polyglutamine toxicity in Drosophila. Science 287, 1837–1840 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Morley, J. F., Brignull, H. R., Weyers, J. J. & Morimoto, R. I. The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 99, 10417–10422 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Chan, H. Y., Warrick, J. M., Gray-Board, G. L., Paulson, H. L. & Bonini, N. M. Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy and modulation of protein solubility in Drosophila. Hum. Mol. Genet. 9, 2811–2820 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Muchowski, P. J. et al. Hsp70 and Hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc. Natl Acad. Sci. USA 97, 7841–7846 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Willingham, S., Outeiro, T. F., DeVit, M. J., Lindquist, S. L. & Muchowski, P. J. Yeast genes that enhance the toxicity of a mutant huntingtin fragment or α-synuclein. Science 302, 1769–1772 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Giorgini, F., Guidetti, P., Nguyen, Q., Bennett, S. C. & Muchowski, P. J. A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease. Nature Genet. 37, 526–531 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Nollen, E. A. et al. Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation. Proc. Natl Acad. Sci. USA 101, 6403–6408 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Steffan, J. S. et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413, 739–743 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Craufurd, D., Dodge, A., Kerzin-Storrar, L. & Harris, R. Uptake of presymptomatic predictive testing for Huntington's disease. Lancet 2, 603–605 (1989).

    Article  CAS  PubMed  Google Scholar 

  • Morris, M. J., Tyler, A., Lazarou, L., Meredith, L. & Harper, P. S. Problems in genetic prediction for Huntington's disease. Lancet 2, 601–603 (1989).

    Article  CAS  PubMed  Google Scholar 

  • Bloch, M., Adam, S., Wiggins, S., Huggins, M. & Hayden, M. R. Predictive testing for Huntington disease in Canada: the experience of those receiving an increased risk. Am. J. Med. Genet. 42, 499–507 (1992).

    Article  CAS  PubMed  Google Scholar 

  • Brandt, J. et al. Presymptomatic diagnosis of delayed-onset disease with linked DNA markers. The experience in Huntington's disease. JAMA 261, 3108–3114 (1989).

    Article  CAS  PubMed  Google Scholar 

  • Huggins, M. et al. Predictive testing for Huntington disease in Canada: adverse effects and unexpected results in those receiving a decreased risk. Am. J. Med. Genet. 42, 508–515 (1992).

    Article  CAS  PubMed  Google Scholar 

  • International Huntington Association and the World Federation of Neurology Research Group on Huntington's Chorea. Guidelines for the molecular genetics predictive test in Huntington's disease. J. Med. Genet. 31, 555–559 (1994).

  • Evers-Kiebooms, G. et al. Predictive DNA-testing for Huntington's disease and reproductive decision making: a European collaborative study. Eur. J. Hum. Genet. 10, 167–176 (2002).

    Article  PubMed  Google Scholar 

  • Harper, P. S., Lim, C. & Craufurd, D. Ten years of presymptomatic testing for Huntington's disease: the experience of the UK Huntington's Disease Prediction Consortium. J. Med. Genet. 37, 567–571 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tibben, A. in Huntington's Disease (eds Bates, G. P., Harper, P. S. & Jones, A. L.) 198–248 (Oxford Univ. Press, Oxford, 2002).

    Google Scholar 

  • Creighton, S. et al. Predictive, pre-natal and diagnostic genetic testing for Huntington's disease: the experience in Canada from 1987 to 2000. Clin. Genet. 63, 462–475 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Clarke, A. The genetic testing of children. Working Party of the Clinical Genetics Society (UK). J. Med. Genet. 31, 785–797 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Benjamin, C. M. & Lashwood, A. United Kingdom experience with presymptomatic testing of individuals at 25% risk for Huntington's disease. Clin. Genet. 58, 41–49 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Simpson, S. A. & Harper, P. S. Prenatal testing for Huntington's disease: experience within the UK 1994–1998. J. Med. Genet. 38, 333–335 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moutou, C., Gardes, N. & Viville, S. New tools for preimplantation genetic diagnosis of Huntington's disease and their clinical applications. Eur. J. Hum. Genet. 12, 1007–1014 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Harper, S. Q. et al. RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model. Proc. Natl Acad. Sci. USA 102, 5820–5825 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Bates, G. P. & Hockly, E. Experimental therapeutics in Huntington's disease: are models useful for therapeutic trials? Curr. Opin. Neurol. 16, 465–470 (2003).

    PubMed  Google Scholar 

  • Hockly, E. et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc. Natl Acad. Sci. USA 100, 2041–2046. (2003).

    Article  CAS  PubMed  Google Scholar 

  • Ferrante, R. J. et al. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice. J. Neurosci. 23, 9418–9427 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Gardian, G. et al. Neuroprotective effects of phenylbutyrate in the N171–82Q transgenic mouse model of Huntington's disease. J. Biol. Chem. 280, 556–563 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Agrawal, N. et al. Identification of combinatorial drug regimens for treatment of Huntington's disease using Drosophila. Proc. Natl Acad. Sci. USA 102, 3777–3781 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Heiser, V. et al. Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay. Proc. Natl Acad. Sci. USA 99 (Suppl. 4), 16400–16406 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Zhang, X. et al. A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo. Proc. Natl Acad. Sci. USA 102, 892–897 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Wang, J., Gines, S., MacDonald, M. E. & Gusella, J. F. Reversal of a full-length mutant huntingtin neuronal cell phenotype by chemical inhibitors of polyglutamine-mediated aggregation. BMC Neurosci. 6, 1 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huntington Study Group. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease. Neurology 57, 397–404 (2001).

  • MacDonald, M. E. et al. A somatic cell hybrid panel for localizing DNA segments near the Huntington's disease gene. Genomics 1, 29–34 (1987).

    Article  CAS  PubMed  Google Scholar 

  • Smith, B. et al. Isolation of DNA markers in the direction of the Huntington disease gene from the G8 locus. Am. J. Hum. Genet. 42, 335–344 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pritchard, C. A., Casher, D., Uglum, E., Cox, D. R. & Myers, R. M. Isolation and field-inversion gel electrophoresis analysis of DNA markers located close to the Huntington disease gene. Genomics 4, 408–418 (1989).

    Article  CAS  PubMed  Google Scholar 

  • Poustka, A. & Lehrach, H. Jumping libraries and linking libraries: the next generation of molecular tools in mammalian genetics. Trends Genet. 2, 174–179 (1986).

    Article  CAS  Google Scholar 

  • Richards, J. E. et al. Chromosome jumping from D4S10 (G8) toward the Huntington disease gene. Proc. Natl Acad. Sci. USA 85, 6437–6441 (1988).

    Article  CAS  PubMed  Google Scholar 

  • Bucan, M. et al. Physical maps of 4p16.3, the area expected to contain the Huntington disease mutation. Genomics 6, 1–15 (1990).

    Article  CAS  PubMed  Google Scholar 

  • Pohl, T. M. et al. Construction of a NotI linking library and isolation of new markers close to the Huntington's disease gene. Nucleic Acids Res. 16, 9185–9198 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burke, D. T., Carle, G. F. & Olson, M. V. Cloning of large segments of exogenous DNA into yeast by means of artificial chromosome vectors. Science 236, 806–812 (1987).

    Article  CAS  PubMed  Google Scholar 

  • Bates, G. P. et al. Characterization of a yeast artificial chromosome contig spanning the Huntington's disease gene candidate region. Nature Genet. 1, 180–187 (1992).

    Article  CAS  PubMed  Google Scholar 

  • Baxendale, S. et al. A cosmid contig and high resolution restriction map of the 2 megabase region containing the Huntington's disease gene. Nature Genet. 4, 181–186 (1993).

    Article  CAS  PubMed  Google Scholar 

  • Browning, W. Huntington number. Neurographs 1, 1–164 (1908).

    Google Scholar