Skip to main content
PMC home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 1999 Oct;36(10):739–746. doi: 10.1136/jmg.36.10.739

A molecular investigation of true dominance in Huntington's disease

Y Narain 1, A Wyttenbach 1, J Rankin 1, R Furlong 1, D Rubinsztein 1
PMCID: PMC1734229  PMID: 10528852

Abstract

Huntington's disease (HD) is thought to show true dominance, since subjects with two mutant alleles have been reported to have similar ages at onset of disease compared to heterozygous sibs. We have investigated this phenomenon using a cell culture model. Protein aggregate formation was used as an indicator for pathology, as intraneuronal huntingtin inclusions are associated with pathology in vitro and in vivo. We showed that cytoplasmic and nuclear aggregates are formed by constructs comprising part of exon 1 of huntingtin with 41, 51, 66, or 72 CAG repeats, in a rate that correlates with repeat number. No inclusions were seen with 21 CAG repeat constructs. Mutant and wild type huntingtin fragments can be sequestered into inclusions seeded by a mutant huntingtin. Wild type huntingtin did not enhance or interfere with protein aggregation. The rate of protein aggregation was dose dependent for all mutant constructs tested. These experiments suggested a model for the dominance observed in HD; the decrease in the age at onset of a mutant homozygote may be small compared to the variance in the age at onset for that specific repeat number in heterozygotes. Our experiments also provide a model, which may explain the different repeat size ranges seen in patients and healthy controls for the different polyglutamine diseases.


Keywords: Huntington's disease; huntingtin; CAG repeats; true dominance

Full Text

The Full Text of this article is available as a PDF (138.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Brinkman R. R., Mezei M. M., Theilmann J., Almqvist E., Hayden M. R. The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. Am J Hum Genet. 1997 May;60(5):1202–1210. [PMC free article] [PubMed] [Google Scholar]
  2. Burright E. N., Clark H. B., Servadio A., Matilla T., Feddersen R. M., Yunis W. S., Duvick L. A., Zoghbi H. Y., Orr H. T. SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell. 1995 Sep 22;82(6):937–948. doi: 10.1016/0092-8674(95)90273-2. [DOI] [PubMed] [Google Scholar]
  3. Coles R., Caswell R., Rubinsztein D. C. Functional analysis of the Huntington's disease (HD) gene promoter. Hum Mol Genet. 1998 May;7(5):791–800. doi: 10.1093/hmg/7.5.791. [DOI] [PubMed] [Google Scholar]
  4. Cooper J. K., Schilling G., Peters M. F., Herring W. J., Sharp A. H., Kaminsky Z., Masone J., Khan F. A., Delanoy M., Borchelt D. R. Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture. Hum Mol Genet. 1998 May;7(5):783–790. doi: 10.1093/hmg/7.5.783. [DOI] [PubMed] [Google Scholar]
  5. Davies S. W., Turmaine M., Cozens B. A., DiFiglia M., Sharp A. H., Ross C. A., Scherzinger E., Wanker E. E., Mangiarini L., Bates G. P. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell. 1997 Aug 8;90(3):537–548. doi: 10.1016/s0092-8674(00)80513-9. [DOI] [PubMed] [Google Scholar]
  6. Duyao M. P., Auerbach A. B., Ryan A., Persichetti F., Barnes G. T., McNeil S. M., Ge P., Vonsattel J. P., Gusella J. F., Joyner A. L. Inactivation of the mouse Huntington's disease gene homolog Hdh. Science. 1995 Jul 21;269(5222):407–410. doi: 10.1126/science.7618107. [DOI] [PubMed] [Google Scholar]
  7. Dürr A., Hahn-Barma V., Brice A., Pêcheux C., Dodé C., Feingold J. Homozygosity in Huntington's disease. J Med Genet. 1999 Feb;36(2):172–173. [PMC free article] [PubMed] [Google Scholar]
  8. Farrer L. A., Cupples L. A., Wiater P., Conneally P. M., Gusella J. F., Myers R. H. The normal Huntington disease (HD) allele, or a closely linked gene, influences age at onset of HD. Am J Hum Genet. 1993 Jul;53(1):125–130. [PMC free article] [PubMed] [Google Scholar]
  9. Fisher L. J. Neural precursor cells: applications for the study and repair of the central nervous system. Neurobiol Dis. 1997;4(1):1–22. doi: 10.1006/nbdi.1997.0137. [DOI] [PubMed] [Google Scholar]
  10. Goldfarb L. G., Vasconcelos O., Platonov F. A., Lunkes A., Kipnis V., Kononova S., Chabrashvili T., Vladimirtsev V. A., Alexeev V. P., Gajdusek D. C. Unstable triplet repeat and phenotypic variability of spinocerebellar ataxia type 1. Ann Neurol. 1996 Apr;39(4):500–506. doi: 10.1002/ana.410390412. [DOI] [PubMed] [Google Scholar]
  11. Hackam A. S., Singaraja R., Zhang T., Gan L., Hayden M. R. In vitro evidence for both the nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington's disease. Hum Mol Genet. 1999 Jan;8(1):25–33. doi: 10.1093/hmg/8.1.25. [DOI] [PubMed] [Google Scholar]
  12. Hodgson J. G., Agopyan N., Gutekunst C. A., Leavitt B. R., LePiane F., Singaraja R., Smith D. J., Bissada N., McCutcheon K., Nasir J. A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron. 1999 May;23(1):181–192. doi: 10.1016/s0896-6273(00)80764-3. [DOI] [PubMed] [Google Scholar]
  13. Igarashi S., Koide R., Shimohata T., Yamada M., Hayashi Y., Takano H., Date H., Oyake M., Sato T., Sato A. Suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated DRPLA protein with an expanded polyglutamine stretch. Nat Genet. 1998 Feb;18(2):111–117. doi: 10.1038/ng0298-111. [DOI] [PubMed] [Google Scholar]
  14. Klement I. A., Skinner P. J., Kaytor M. D., Yi H., Hersch S. M., Clark H. B., Zoghbi H. Y., Orr H. T. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell. 1998 Oct 2;95(1):41–53. doi: 10.1016/s0092-8674(00)81781-x. [DOI] [PubMed] [Google Scholar]
  15. Lerer I., Merims D., Abeliovich D., Zlotogora J., Gadoth N. Machado-Joseph disease: correlation between the clinical features, the CAG repeat length and homozygosity for the mutation. Eur J Hum Genet. 1996;4(1):3–7. doi: 10.1159/000472162. [DOI] [PubMed] [Google Scholar]
  16. Li H., Li S. H., Cheng A. L., Mangiarini L., Bates G. P., Li X. J. Ultrastructural localization and progressive formation of neuropil aggregates in Huntington's disease transgenic mice. Hum Mol Genet. 1999 Jul;8(7):1227–1236. doi: 10.1093/hmg/8.7.1227. [DOI] [PubMed] [Google Scholar]
  17. Lunkes A., Mandel J. L. A cellular model that recapitulates major pathogenic steps of Huntington's disease. Hum Mol Genet. 1998 Sep;7(9):1355–1361. doi: 10.1093/hmg/7.9.1355. [DOI] [PubMed] [Google Scholar]
  18. Martindale D., Hackam A., Wieczorek A., Ellerby L., Wellington C., McCutcheon K., Singaraja R., Kazemi-Esfarjani P., Devon R., Kim S. U. Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates. Nat Genet. 1998 Feb;18(2):150–154. doi: 10.1038/ng0298-150. [DOI] [PubMed] [Google Scholar]
  19. Matsumura R., Futamura N., Fujimoto Y., Yanagimoto S., Horikawa H., Suzumura A., Takayanagi T. Spinocerebellar ataxia type 6. Molecular and clinical features of 35 Japanese patients including one homozygous for the CAG repeat expansion. Neurology. 1997 Nov;49(5):1238–1243. doi: 10.1212/wnl.49.5.1238. [DOI] [PubMed] [Google Scholar]
  20. Myers R. H., Cupples L. A., Schoenfeld M., D'Agostino R. B., Terrin N. C., Goldmakher N., Wolf P. A. Maternal factors in onset of Huntington disease. Am J Hum Genet. 1985 May;37(3):511–523. [PMC free article] [PubMed] [Google Scholar]
  21. Nasir J., Floresco S. B., O'Kusky J. R., Diewert V. M., Richman J. M., Zeisler J., Borowski A., Marth J. D., Phillips A. G., Hayden M. R. Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell. 1995 Jun 2;81(5):811–823. doi: 10.1016/0092-8674(95)90542-1. [DOI] [PubMed] [Google Scholar]
  22. Paulson H. L., Perez M. K., Trottier Y., Trojanowski J. Q., Subramony S. H., Das S. S., Vig P., Mandel J. L., Fischbeck K. H., Pittman R. N. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron. 1997 Aug;19(2):333–344. doi: 10.1016/s0896-6273(00)80943-5. [DOI] [PubMed] [Google Scholar]
  23. Paulson H. L. Protein fate in neurodegenerative proteinopathies: polyglutamine diseases join the (mis)fold. Am J Hum Genet. 1999 Feb;64(2):339–345. doi: 10.1086/302269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Perez M. K., Paulson H. L., Pendse S. J., Saionz S. J., Bonini N. M., Pittman R. N. Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. J Cell Biol. 1998 Dec 14;143(6):1457–1470. doi: 10.1083/jcb.143.6.1457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Perutz M. F. Glutamine repeats and neurodegenerative diseases: molecular aspects. Trends Biochem Sci. 1999 Feb;24(2):58–63. doi: 10.1016/s0968-0004(98)01350-4. [DOI] [PubMed] [Google Scholar]
  26. Ranen N. G., Stine O. C., Abbott M. H., Sherr M., Codori A. M., Franz M. L., Chao N. I., Chung A. S., Pleasant N., Callahan C. Anticipation and instability of IT-15 (CAG)n repeats in parent-offspring pairs with Huntington disease. Am J Hum Genet. 1995 Sep;57(3):593–602. [PMC free article] [PubMed] [Google Scholar]
  27. Reddy P. H., Williams M., Charles V., Garrett L., Pike-Buchanan L., Whetsell W. O., Jr, Miller G., Tagle D. A. Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nat Genet. 1998 Oct;20(2):198–202. doi: 10.1038/2510. [DOI] [PubMed] [Google Scholar]
  28. Rubinsztein D. C., Leggo J., Chiano M., Dodge A., Norbury G., Rosser E., Craufurd D. Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3872–3876. doi: 10.1073/pnas.94.8.3872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rubinsztein D. C., Wyttenbach A., Rankin J. Intracellular inclusions, pathological markers in diseases caused by expanded polyglutamine tracts? J Med Genet. 1999 Apr;36(4):265–270. [PMC free article] [PubMed] [Google Scholar]
  30. Sanpei K., Takano H., Igarashi S., Sato T., Oyake M., Sasaki H., Wakisaka A., Tashiro K., Ishida Y., Ikeuchi T. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet. 1996 Nov;14(3):277–284. doi: 10.1038/ng1196-277. [DOI] [PubMed] [Google Scholar]
  31. Sato K., Kashihara K., Okada S., Ikeuchi T., Tsuji S., Shomori T., Morimoto K., Hayabara T. Does homozygosity advance the onset of dentatorubral-pallidoluysian atrophy? Neurology. 1995 Oct;45(10):1934–1936. doi: 10.1212/wnl.45.10.1934. [DOI] [PubMed] [Google Scholar]
  32. Saudou F., Finkbeiner S., Devys D., Greenberg M. E. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell. 1998 Oct 2;95(1):55–66. doi: 10.1016/s0092-8674(00)81782-1. [DOI] [PubMed] [Google Scholar]
  33. Scherzinger E., Sittler A., Schweiger K., Heiser V., Lurz R., Hasenbank R., Bates G. P., Lehrach H., Wanker E. E. Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington's disease pathology. Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4604–4609. doi: 10.1073/pnas.96.8.4604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Snell R. G., MacMillan J. C., Cheadle J. P., Fenton I., Lazarou L. P., Davies P., MacDonald M. E., Gusella J. F., Harper P. S., Shaw D. J. Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease. Nat Genet. 1993 Aug;4(4):393–397. doi: 10.1038/ng0893-393. [DOI] [PubMed] [Google Scholar]
  35. Sobue G., Doyu M., Nakao N., Shimada N., Mitsuma T., Maruyama H., Kawakami S., Nakamura S. Homozygosity for Machado-Joseph disease gene enhances phenotypic severity. J Neurol Neurosurg Psychiatry. 1996 Mar;60(3):354–356. doi: 10.1136/jnnp.60.3.354-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Warrick J. M., Paulson H. L., Gray-Board G. L., Bui Q. T., Fischbeck K. H., Pittman R. N., Bonini N. M. Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila. Cell. 1998 Jun 12;93(6):939–949. doi: 10.1016/s0092-8674(00)81200-3. [DOI] [PubMed] [Google Scholar]
  37. Wexler N. S., Young A. B., Tanzi R. E., Travers H., Starosta-Rubinstein S., Penney J. B., Snodgrass S. R., Shoulson I., Gomez F., Ramos Arroyo M. A. Homozygotes for Huntington's disease. Nature. 1987 Mar 12;326(6109):194–197. doi: 10.1038/326194a0. [DOI] [PubMed] [Google Scholar]
  38. White J. K., Auerbach W., Duyao M. P., Vonsattel J. P., Gusella J. F., Joyner A. L., MacDonald M. E. Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion. Nat Genet. 1997 Dec;17(4):404–410. doi: 10.1038/ng1297-404. [DOI] [PubMed] [Google Scholar]
  39. 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. Nat Genet. 1995 Oct;11(2):155–163. doi: 10.1038/ng1095-155. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES