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Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;8(4):699–714. doi: 10.1111/j.1750-3639.1998.tb00196.x

Transgenic Mice in the Study of Polyglutamine Repeat Expansion Diseases

Gillian P Bates 1,, Laura Mangiarini 1, Stephen W Davies 2
PMCID: PMC8098430  PMID: 9804379

Abstract

An increasing number of neurodegenerative diseases, including Huntington's disease (HD), have been found to be caused by a CAG/polyglutamine expansion. We have generated a mouse model of HD by the introduction of exon 1 of the human HD gene carrying highly expanded CAG repeats into the mouse germ line. These mice develop a progressive neurological phenotype. Neuronal intranuclear inclusions (NII) that are immunoreactive for huntingtin and ubiquitin have been found in the brains of symptomatic mice. In vitro analysis indicates that the inclusions are formed through self aggregation via the polyglutamine repeat into amyloid‐like fibrils composed of a cross β‐sheet structure that has been termed a polar zipper. Analysis of patient material and other transgenic lines has now shown NII to be a common feature of all of these diseases. In the transgenic models, inclusions are present prior to the onset of symptoms suggesting a causal relationship. In contrast, neurodegeneration occurs after the onset of the phenotype indicating that the symptoms are caused by a neuronal dysfunction rather than a primary cell death.

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References

  • 1. Ambrose CM , Duyao MP , Barnes G , Bates GP , Lin CS , Srinidhi J , Baxendale S , Hummerich H , Lehrach H , Altherr M , Wasmuth J , Buckler A , Church D , Housman D , Berks M , Micklem G , Durbin R , Dodge A , Read A , Gusella J , MacDonald ME ( 1993. ) Structure and expression of the Huntington's disease gene: evidence against simple inactivation due to an expanded CAG repeat . Somatic Cell Mol. Genet. 20 : 27 – 38 . [DOI] [PubMed] [Google Scholar]
  • 2. Banfi S , Servadio A , Chung M , Kwiatkowski T , McCall AE , Duvick L , Shen Y , Roth EJ , Orr HT , Zoghbi HY ( 1994. ) Identification and characterisation of the gene causing type 1 spinocerebellar ataxia . Nature Genet. 7 : 513 – 520 . [DOI] [PubMed] [Google Scholar]
  • 3. Baxendale S , Abdulla S , Elgar G , Bucks D , Berks M , Micklem G , Durbin R , Bates G , Brenner S , Beck S , Lehrach H ( 1995. ) Comparative sequence analysis of the human and puffer fish Huntington's disease gene . Nature Genet. 10 : 67 – 75 . [DOI] [PubMed] [Google Scholar]
  • 4. Becher MW , Kotzuk JA , Sharp AH , Davies SW , Bates GP , Price DL , Ross CA ( 1998. ) Intranuclear neuronal inclusions in Huntington's disease and dentatorubral pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG repeat length . Neurobiol. Dis. 4 : 387 – 397 . [DOI] [PubMed] [Google Scholar]
  • 5. Bertaux F , Sharp AH , Ross CA , Lehrach H , Bates GP , Wanker EE ( 1998. ) HAP1‐huntingtin interactions do not contribute to the molecular pathology in Huntington's disease transgenic mice . FEBS Lett. 426 : 229 – 232 . [DOI] [PubMed] [Google Scholar]
  • 6. Burke JR , Enghild JJ , Martin ME , Jou Y‐S , Myers RM , Roses AD , Vance JM , Strittmatter WJ ( 1996. ) Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH . Nature Med. 2 : 347 – 350 . [DOI] [PubMed] [Google Scholar]
  • 7. Burright EN , Clark HB , Servadio A , Matilla T , Fedderson RM , Yunis WS , Duvick LA , Zoghbi HY , Orr HT ( 1995. ) SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat . Cell 82 : 937 – 948 . [DOI] [PubMed] [Google Scholar]
  • 8. Caputo CB , Fraser PE , Sobel IE , Krischner DA ( 1992. ) Amyloid‐like properties of a synthetic peptide corresponding to the carboxy terminus of β‐amyloid protein precursor . Arch. Biochem. Biophys. 292 : 199 – 205 . [DOI] [PubMed] [Google Scholar]
  • 9. Cha J‐HJ , Kosinski CM , Kerner JA , Alsdorf SA , Mangiarini L , Davies SW , Penney JB , Bates GP , Young AB ( 1998. ) Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human Huntington's disease gene . Proc. Natl. Acad. Sci. USA 95 : 6480 – 6485 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Chang C , Kokontis J , Liao S ( 1988. ) Structural analysis of complementary DNA and amino acid sequences of human and rat androgen receptors . Proc. Natl. Acad. Sci. USA 85 : 7211 – 7215 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Clark HB , Burright EN , Yunis WS , Larson S , Wilcox C , Hartman B , Matilla A , Zoghbi HY , Orr HT ( 1997. ) Purkinje cell expression of a mutant alllele of SCA1 in transgenic mice leads to disparate effects on motor behaviors, followed by a progressive cerebellar dysfunction and histological alterations . J. Neurosci. 17 : 7385 – 7395 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Cooper JK , Schilling G , Peters MF , Herring WJ , Sharp AH , Kaminsky Z , Masone J , Khan FA , Delanoy M , Borchelt DR , Dawson VL , Dawson TM , Ross CA ( 1998. ) Truncated N‐terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture . Hum. Mol. Genet. 7 : 783 – 790 . [DOI] [PubMed] [Google Scholar]
  • 13. 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 N , Ruberg M , Agid Y , Mandel JL , Brice A ( 1997. ) Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion . Nature Genet. 17 : 65 – 70 . [DOI] [PubMed] [Google Scholar]
  • 14. Davies SW , Beardsall K , Turmaine M , DiFiglia M , Aronin N , Bates GP ( 1998. ) Neuronal intranuclear inclusions (NII), the common neuropathology of triplet repeat disorders with polyglutamine repeeat expansions . Lancet 351 : 131 – 133 . [DOI] [PubMed] [Google Scholar]
  • 15. Davies SW , Turmaine M , Cozens BA , DiFiglia M , Sharp AH , Ross CA , Scherzinger E , Wanker EE , Mangiarini L , Bates GP ( 1997. ) Formation of neuronal intranuclear inclusions (NII) underlies the neurological dysfunction in mice transgenic for the HD mutation . Cell 90 : 537 – 548 . [DOI] [PubMed] [Google Scholar]
  • 16. de la Monte SM , Vonsattel J‐P , Richardson EP ( 1988. ) Morphometric demonstration of atrophic changes in the cerebral cortex, white matter and neostriatum in Huntington's disease . J. Neuropathol. Exp. Neurol. 47 : 516 – 525 . [DOI] [PubMed] [Google Scholar]
  • 17. DiFiglia M , Sapp E , Chase KO , Davies SW , Bates GP , Vonsattel J‐P , Aronin N ( 1997. ) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain . Science 277 : 1990 – 1993 . [DOI] [PubMed] [Google Scholar]
  • 18. Duyao M , Ambrose C , Myers R , Novelletto A , Persichetti F , Frontali M , Folstein S , Ross C , Franz M , Abbott M , Gray J , Conneally MP , Young A , Penney J , Hollingsworth Z , Shoulson I , Lazzarini A , Falek A , Koroshetz W , Sax D , Bird E , Vonsattel J , Bonilla E , Alvir J , Conde JB , Cha J‐H , Dure L , Gomez F , Ramos M , Sanchez‐Ramos J , Snodgrass S , De Young M , Wexler N , Moscowitz C , Penchaszadeh G , MacFarlane H , Anderson M , Jenkins B , Srinidhi J , Barnes G , Gusella J , MacDonald M ( 1993. ) Trinucleotide repeat length instability and age of onset in Huntington's disease . Nature Genet. 4 : 387 – 392 . [DOI] [PubMed] [Google Scholar]
  • 19. Duyao MP , Auerbach AA , Ryan A , Persichetti F , Barnes GT , McNeil SM , Ge P , Vonstattel J‐P , Gusella JF , Joyner AL , MacDonald ME ( 1995. ) Inactivation of the mouse Huntington's disease gene homolog Hdh . Science 269 : 407 – 410 . [DOI] [PubMed] [Google Scholar]
  • 20. Ferrante RJ , Gutekunst C‐A , Persichetti F , McNeil SM , Kowall NW , Gusella JF , MacDonald ME , Beal MF , Hersch SM ( 1997. ) Heterogeneous topographic and cellular distribution of huntingtin expression in the normal human neostriatum . J. Neurosci. 17 : 3052 – 3063 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Goldberg YP , Nicholson DW , Rasper DM , Kalchman MA , Koide HB , Graham RK , Bromm M , Kazemi‐Esfarjani P , Thornberry NA , Vaillancourt JP , Hayden MR ( 1996. ) Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract . Nature Genet. 13 : 442 – 449 . [DOI] [PubMed] [Google Scholar]
  • 22. Green H ( 1993. ) Human genetic diseases due to codon reiteration: relationship to an evolutionary mechanism . Cell 74 : 955 – 956 . [DOI] [PubMed] [Google Scholar]
  • 23. HDCRG ( 1993. ) A novel gene containing a trinucleotide repeat that is unstable on Huntington's disease chromosomes . Cell 72 : 971 – 983 . [DOI] [PubMed] [Google Scholar]
  • 24. Hochstrasser M ( 1996. ) Ubiquitin‐dependent protein degradation . Ann. Rev. Genet. 30 : 405 – 439 . [DOI] [PubMed] [Google Scholar]
  • 25. Holmberg M , Duyckaerts C , Durr A , Cancel G , Gourfinkel‐An I , Damier P , Faucheux B , Trottier Y , Hirsch EC , Agid Y , Brice A ( 1998. ) Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions . Hum. Mol. Genet. 7 : 913 – 918 . [DOI] [PubMed] [Google Scholar]
  • 26. Igarashi S , Koide R , Shimohata T , Yamada M , Hayashi Y , Takano H , Date H , Oyake M , Sato T , Sato A , Egawa S , Ikeuchi T , Tanaka H , Nakano R , Tanaka K , Hozumi I , Inuzuka T , Takahashi H , Tsuji S ( 1998. ) Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch . Nature Genet. 18 : 111 – 117 . [DOI] [PubMed] [Google Scholar]
  • 27. Ikeda H , Yamaguchi M , Sugai S , Aze Y , Narumiya S , Kakizuka A ( 1996. ) Expanded polyglutamine in the Machado‐Joseph disease protein induces cell death in vitro and in vivo . Nature Genet. 13 : 196 – 202 . [DOI] [PubMed] [Google Scholar]
  • 28. Imbert G , Sandou F , Yvert G , Devys D , Trottier Y , Garnier J‐M , Weber C , Mandel J‐L , Cancel G , Abbas N , Durr A , Didierjean O , Stevanin G , Agid Y , Brice A ( 1996. ) Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats . Nature Genet. 14 : 285 – 291 . [DOI] [PubMed] [Google Scholar]
  • 29. Kalchman MA , Graham RK , Xia G , Koide HB , Hodgson JG , Graham KC , Goldberg YP , Gietz RD , Pickart CM , Hayden MR ( 1996. ) Huntingtin is ubiquinated and interacts with a specific ubiquitin‐conjugating enzyme . J. Biol. Chem. 271 : 19385 – 19394 . [DOI] [PubMed] [Google Scholar]
  • 30. Kalchman MA , Koide HB , McCutcheon K , Graham RK , Nichol K , Nishiyama K , Kazemi‐Esfariani P , Lynn FC , Wellington C , Metzler M , Goldberg YP , Kanazawa I , Gietz RD , Hayden MR ( 1997. ) HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane‐associated huntingtin in the brain . Nature Genet. 16 : 44 – 53 . [DOI] [PubMed] [Google Scholar]
  • 31. Kawaguchi Y , Okamoto T , Taniwaki M , Aizawa M , Inoue M , Katayama S , Kawakami H , Nakamura S , Nishimura M , Akiguchi I , Kimura J , Narumiya S , Kakizuka A ( 1994. ) CAG expansions in a novel gene for Machado‐Joseph disease at chromosome 14q32.1 . Nature Genet. 8 : 221 – 228 . [DOI] [PubMed] [Google Scholar]
  • 32. Koide R , Ikeuchi T , Onodera O , Tanaka H , Igarashi S , Endo K , Takahashi H , Kondo R , Ishikawa A , Hayashi T , Saito M , Tomoda A , Miike T , Naito H , Ikuta F , Tsuji S ( 1994. ) Unstable expansion of CAG repeat in hereditary dentatorubral‐pallidoluysian atrophy (DRPLA) . Nature Genet. 6 : 9 – 13 . [DOI] [PubMed] [Google Scholar]
  • 33. Kosinski CM , Cha JH , Young AB , Persichetti F , MacDonald M , Gusella JF , Penney JB , Standaert DG ( 1997. ) Huntingtin immunoreactivity in the rat neostriatum: differential accumulation in projection and interneurons . Exp. Neurol. 144 : 239 – 247 . [DOI] [PubMed] [Google Scholar]
  • 34. La Spada AR , Wilson EM , Lubahn DB , Harding AE , Fischbeck KH ( 1991. ) Androgen receptor gene mutations in X‐linked spinal and bulbar muscular atrophy . Nature 352 : 77 – 79 . [DOI] [PubMed] [Google Scholar]
  • 35. Lansbury PT ( 1997. ) Structural neurology: are seeds at the root of neuronal degeneration ? Neuron 19 : 1151 – 1154 . [DOI] [PubMed] [Google Scholar]
  • 36. Li S‐H , Li X‐J ( 1998. ) Aggregation of N‐terminal huntingtin is dependent on the length of its glutamine repeats . Hum. Mol. Genet. 7 : 777 – 782 . [DOI] [PubMed] [Google Scholar]
  • 37. Li X‐J , Li S‐H , Sharp AH , Nucifora FC , Schilling G , Lanahan A , Worley P , Snyder SH , Ross CA ( 1995. ) A huntingtin‐associated protein enriched in brain with implications for pathology . Nature 378 : 398 – 402 . [DOI] [PubMed] [Google Scholar]
  • 38. Mangiarini L , Sathasivam K , Mahal A , Mott R , Seller M , Bates GP ( 1997. ) Instability of highly expanded CAG repeats in transgenic mice is related to expression of the transgene . Nature Genet. 15 : 197 – 200 . [DOI] [PubMed] [Google Scholar]
  • 39. Mangiarini L , Sathasivam K , Seller M , Cozens B , Harper A , Hetherington C , Lawton M , Trottier Y , Lehrach H , Davies SW , Bates GP ( 1996. ) Exon 1 of the Huntington's disease gene containing a highly expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice . Cell 87 : 493 – 506 . [DOI] [PubMed] [Google Scholar]
  • 40. Martindale D , Hackman A , Wieczorek A , Ellerby L , Wellington C , McCutcheon K , Singaraja R , Kazemi‐Esfarjani P , Devon R , Kim SU , Bredesen DE , Tufaro F , Hayden MR ( 1998. ) Length of huntingtin and its polyglutamine tract influences localisation and frequency of intracellular aggregates . Nature Genet. 18 : 150 – 154 . [DOI] [PubMed] [Google Scholar]
  • 41. Matilla A , Koshy BT , Cummings CJ , Isobe T , Orr HT , Zoghbi HY ( 1997. ) The cerebellar leucine‐rich acidic nuclear protein interacts with ataxin‐1 . Nature 389 : 974 – 978 . [DOI] [PubMed] [Google Scholar]
  • 42. Nagafuchi S , Yanagisawa H , Ohsaki E , Shirayama T , Tadokoro K , Inoue T , Yamada M ( 1994. ) Structure and expression of the gene responsible for the triplet repeat disorder, dentatorubral and pallidoluysian atrophy (DRPLA) . Nature Genet. 8 : 177 – 182 . [DOI] [PubMed] [Google Scholar]
  • 43. Nagafuchi S , Yanagisawa H , Sato K , Shirayama T , Ohsaki E , Bundo M , Takeda T , Tadokoro K , Kondo I , Murayama N , Tanaka Y , Kikushima H , Umino K , Kurosawa H , Furukawa T , Nihei K , Inoue T , Sano A , Komure O , Takahashi M , Yoshizawa T , Kanazawa I , Yamada M ( 1994. ) Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p . Nature Genet. 6 : 14 – 18 . [DOI] [PubMed] [Google Scholar]
  • 44. Nasir J , Floresco SB , O'Kusky JR , Diewert VM , Richman JM , Zeisler J , Borowski A , Marth JD , Phillips AG , Hayden MR ( 1995. ) Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes . Cell 81 : 811 – 823 . [DOI] [PubMed] [Google Scholar]
  • 45. Ordway JM , Tallaksen‐Greene S , Gutekunst C‐A , Bernstein EM , Cearley JA , Wiener HW , Dure LS IV , Lindsey R , Hersch SM , Jope RS , Albin RL , Detloff PJ ( 1997. ) Ectopically expressed CAG repeats cause intranuclear inclusions and a progressive late onset neurological phenotype in the mouse . Cell 91 : 753 – 763 . [DOI] [PubMed] [Google Scholar]
  • 46. Orr HT , Chung M , Banfi S , Kwiatkowski TJ , Jr. , Servadio A , Beaudet AL , McCall AE , Duvick LA , Ranum LPW , Zoghbi HY ( 1993. ) Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1 . Nature Genet. 4 : 221 – 226 . [DOI] [PubMed] [Google Scholar]
  • 47. Paulson HL , Perez MK , Trottier Y , Trojanowski JQ , Subramony SH , Das SS , Vig P , Mandel J‐L , Fischbeck KH , Pittman RN ( 1997. ) Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3 . Neuron 19 : 1 – 20 . [DOI] [PubMed] [Google Scholar]
  • 48. Perutz MF , Johnson T , Suzuki M , Finch JT ( 1994. ) Glutamine repeats as polar zippers: Their possible role in inherited neurodegenerative diseases . Proc. Natl. Acad. Sci. USA 91 : 5355 – 5358 . [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Pulst S‐M , Nechiporuk A , Nechiporuk T , Gispert S , Chen X‐N , Lopes‐Cendes I , Pearlman S , Starkman S , Orozco‐Diaz G , Lunkes A , de Jong P , Rouleau GA , Auburger G , Korenberg JR , Figueroa C , Sahba S ( 1996. ) Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2 . Nature Genet. 14 : 269 – 276 . [DOI] [PubMed] [Google Scholar]
  • 50. Roizin L , Stellar S , Liu JC ( 1979. ) Neuronal nuclear‐cytoplasmic changes in Huntington's chorea: electron microscope investigations . In : Advances in Neurology , Chase , T. N. , Wexler , N. S. & Barbeau , A. , ( Eds. ), pp. 95 – 122 , Raven Press; , New York . [Google Scholar]
  • 51. Roos RAC , Bots GTAM ( 1983. ) Nuclear membrane indentations in Huntington's chorea . J. Neurolog. Sci. 61 : 37 – 47 . [DOI] [PubMed] [Google Scholar]
  • 52. Ross CA ( 1995. ) When more is less: pathogenesis of glutamine repeat neurodegenerative diseases . Neuron 15 : 493 – 496 . [DOI] [PubMed] [Google Scholar]
  • 53. Ross CA ( 1997. ) Intranuclear neuronal inclusions: a common pathogenic mechanism for glutamine‐repeat neurodegenerative diseases ? Neuron 19 : 1147 – 1150 . [DOI] [PubMed] [Google Scholar]
  • 54. Sampei K , Takano H , Igarashi S , Sato T , Oyake M , Sasaki H , Wakisaka A , Tashiro K , Ishida Y , Ikeuchi T , Koide R , Saito M , Sato A , Tanaka T , Hanyu S , Takiyama Y , Nishizawa M , Shimizu N , Nomura Y , Segawa M , Iwabuchi K , Eguchi I , Tanaka H , Takahashi H , Tsuji S ( 1996. ) Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT . Nature Genet. 14 : 277 – 284 . [DOI] [PubMed] [Google Scholar]
  • 55. Sapp E , Schwarz C , Chase K , Bhide PG , Young AB , Penney J , Vonsattel JP , Aronin N , DiFiglia M ( 1997. ) Huntingtin localization in brains of normal and Huntington's disease patients . Ann. Neurol. 42 : 604 – 612 . [DOI] [PubMed] [Google Scholar]
  • 56. Scherzinger E , Lurz R , Turmaine M , Mangiarini L , Hollenbach B , Hasenbank R , Bates GP , Davies SW , Lehrach H , Wanker EE ( 1997. ) Huntingtin encoded polyglutamine expansions form amyloid‐like protein aggregates in vitro and in vivo . Cell 90 : 549 – 558 . [DOI] [PubMed] [Google Scholar]
  • 57. Skinner PJ , Koshy BT , Cummings CJ , Klement IA , Helin K , Servadio A , Zoghbi HY , Orr HT ( 1997. ) Ataxin‐1 with an expanded glutamine tract alters nuclear matrix‐associated structures . Nature 389 : 971 – 974 . [DOI] [PubMed] [Google Scholar]
  • 58. Telenius H , Kremer HPH , Theilmann J , Andrew SE , Almquist E , Anvret M , Greenberg C , Greenberg J , Lucotte G , Squitieri F , Starr E , Goldberg YP , Hayden MR ( 1993. ) 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 . [DOI] [PubMed] [Google Scholar]
  • 59. Tellez‐Nagel I , Johnson B , Terry RD ( 1974. ) Studies on brain biopsies of patients with Huntington's chorea . J. Neurocytol. 3 : 308 – 332 . [DOI] [PubMed] [Google Scholar]
  • 60. Trottier Y , Lutz Y , Stevanin G , Imbert G , Devys D , Cancel G , Sandou F , Weber C , David G , Tora L , Agid Y , Brice A , Mandel J‐L ( 1995. ) Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias . Nature 378 : 403 – 406 . [DOI] [PubMed] [Google Scholar]
  • 61. Wanker EE , Rovira C , Scherzinger E , Hasenbank R , Walter S , Tait D , Colicelli J , Lehrach H ( 1997. ) HIP‐1: A huntingtin interacting protein isolated by the yeast two‐hybrid system . Hum. Mol. Genet. 6 : 487 – 495 . [DOI] [PubMed] [Google Scholar]
  • 62. Young AB ( 1998. ) Huntington's disease and other trinucleotide repeat disorders . In : Molecular Neurology , Martin , J. B. , ( Eds. ), pp. 35 – 54 , Scientific American Inc. , New York . [Google Scholar]
  • 63. Zeitlin S , Liu J‐P , Chapman DL , Papaioannou VE , Estradiatis A ( 1995. ) Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue . Nature Genet. 11 : 155 – 163 . [DOI] [PubMed] [Google Scholar]
  • 64. Zhuchenko O , Bailey J , Bonnen P , Ashizawa T , Stockton D , Amos C , Dobyns WB , Subramony SH , Zoghbi HY , Li CC ( 1997. ) Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A‐voltage dependent calcium channel . Nature Genet. 15 : 62 – 69 . [DOI] [PubMed] [Google Scholar]

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