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Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 1998 Jun;64(6):758–762. doi: 10.1136/jnnp.64.6.758

Genetic polymorphisms adjacent to the CAG repeat influence clinical features at onset in Huntington's disease

I Vuillaume 1, P Vermersch 1, A Destee 1, H Petit 1, B Sablonniere 1
PMCID: PMC2170128  PMID: 9647305

Abstract

OBJECTIVES—To evaluate possible influences of CCG and Δ2642 glutamic acid polymorphisms adjacent to the (CAG)n trinucleotide repeat in Huntington's disease gene IT15 on some clinical features (age and symptoms) at onset.
METHODS—84 patients and a control group of 68 unaffected relatives were studied. Patients all belonged to a group of affected persons tested for molecular confirmation of Huntington's disease. The length of the CAG repeat sequence in the IT15 gene and the adjacent CCG and Δ2642 polymorphisms were determined by quantitative polymerase chain reaction.
RESULTS—Two intragenic polymorphisms were studied: (CCG)n and Δ2642 glutamic acid. Patients were classified firstly according to the size of the CCG rich segment adjacent to the CAG repeat into genotype groups CCG 7/7, 7/8, 7/9, 7/10, and 10/10 and then according to Δ2642 polymorphism into genotype groups A/A (absence of the Δ2642 deletion), A/B, and B/B (presence of the Δ2642 deletion in respectively one and two alleles). The presence of Δ2642 mutation was associated with a significant decrease in age at onset, although there was no significant increase in CAG size. A good correlation was found between the (CAG)n trinucleotide repeat size and the age at onset in patients with genotype AA (r2=0.72). Within patients of the A/B genotype group however, a significant correlation was found but with a drop of the r2 value to 0.44. No association was found between age at onset and the CCG polymorphism. Although an increased percentage of patients within the A/A genotype group had a neurological onset, we found no overall significant association between CCG or Δ2642 polymorphisms and the nature of symptoms at onset.
CONCLUSIONS—The Δ2642 glutamic acid polymorphism did not affect CAG repeat size nor the nature of symptoms at onset but seems to influence the age at onset in patients with Huntington's disease.



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Selected References

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  1. Almqvist E., Spence N., Nichol K., Andrew S. E., Vesa J., Peltonen L., Anvret M., Goto J., Kanazawa I., Goldberg Y. P. Ancestral differences in the distribution of the delta 2642 glutamic acid polymorphism is associated with varying CAG repeat lengths on normal chromosomes: insights into the genetic evolution of Huntington disease. Hum Mol Genet. 1995 Feb;4(2):207–214. doi: 10.1093/hmg/4.2.207. [DOI] [PubMed] [Google Scholar]
  2. Ambrose C. M., Duyao M. P., Barnes G., Bates G. P., Lin C. S., Srinidhi J., Baxendale S., Hummerich H., Lehrach H., Altherr M. 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. doi: 10.1007/BF02257483. [DOI] [PubMed] [Google Scholar]
  3. Andrew S. E., Goldberg Y. P., Kremer B., Telenius H., Theilmann J., Adam S., Starr E., Squitieri F., Lin B., Kalchman M. A. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat Genet. 1993 Aug;4(4):398–403. doi: 10.1038/ng0893-398. [DOI] [PubMed] [Google Scholar]
  4. Andrew S. E., Goldberg Y. P., Theilmann J., Zeisler J., Hayden M. R. A CCG repeat polymorphism adjacent to the CAG repeat in the Huntington disease gene: implications for diagnostic accuracy and predictive testing. Hum Mol Genet. 1994 Jan;3(1):65–67. doi: 10.1093/hmg/3.1.65. [DOI] [PubMed] [Google Scholar]
  5. Barron L. H., Rae A., Holloway S., Brock D. J., Warner J. P. A single allele from the polymorphic CCG rich sequence immediately 3' to the unstable CAG trinucleotide in the IT15 cDNA shows almost complete disequilibrium with Huntington's disease chromosomes in the Scottish population. Hum Mol Genet. 1994 Jan;3(1):173–175. doi: 10.1093/hmg/3.1.173. [DOI] [PubMed] [Google Scholar]
  6. Brandt J., Bylsma F. W., Gross R., Stine O. C., Ranen N., Ross C. A. Trinucleotide repeat length and clinical progression in Huntington's disease. Neurology. 1996 Feb;46(2):527–531. doi: 10.1212/wnl.46.2.527. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Claes S., Van Zand K., Legius E., Dom R., Malfroid M., Baro F., Godderis J., Cassiman J. J. Correlations between triplet repeat expansion and clinical features in Huntington's disease. Arch Neurol. 1995 Aug;52(8):749–753. doi: 10.1001/archneur.1995.00540320021009. [DOI] [PubMed] [Google Scholar]
  9. Di Maio L., Squitieri F., Napolitano G., Campanella G., Trofatter J. A., Conneally P. M. Onset symptoms in 510 patients with Huntington's disease. J Med Genet. 1993 Apr;30(4):289–292. doi: 10.1136/jmg.30.4.289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Duyao M., Ambrose C., Myers R., Novelletto A., Persichetti F., Frontali M., Folstein S., Ross C., Franz M., Abbott M. Trinucleotide repeat length instability and age of onset in Huntington's disease. Nat Genet. 1993 Aug;4(4):387–392. doi: 10.1038/ng0893-387. [DOI] [PubMed] [Google Scholar]
  11. Farrer L. A., Conneally P. M. A genetic model for age at onset in Huntington disease. Am J Hum Genet. 1985 Mar;37(2):350–357. [PMC free article] [PubMed] [Google Scholar]
  12. Farrer L. A., Conneally P. M., Yu P. L. The natural history of Huntington disease: possible role of "aging genes". Am J Med Genet. 1984 May;18(1):115–123. doi: 10.1002/ajmg.1320180115. [DOI] [PubMed] [Google Scholar]
  13. Farrer L. A., Cupples L. A., Kiely D. K., Conneally P. M., Myers R. H. Inverse relationship between age at onset of Huntington disease and paternal age suggests involvement of genetic imprinting. Am J Hum Genet. 1992 Mar;50(3):528–535. [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. Gusella J. F., Wexler N. S., Conneally P. M., Naylor S. L., Anderson M. A., Tanzi R. E., Watkins P. C., Ottina K., Wallace M. R., Sakaguchi A. Y. A polymorphic DNA marker genetically linked to Huntington's disease. Nature. 1983 Nov 17;306(5940):234–238. doi: 10.1038/306234a0. [DOI] [PubMed] [Google Scholar]
  16. Illarioshkin S. N., Igarashi S., Onodera O., Markova E. D., Nikolskaya N. N., Tanaka H., Chabrashwili T. Z., Insarova N. G., Endo K., Ivanova-Smolenskaya I. A. Trinucleotide repeat length and rate of progression of Huntington's disease. Ann Neurol. 1994 Oct;36(4):630–635. doi: 10.1002/ana.410360412. [DOI] [PubMed] [Google Scholar]
  17. Kremer B., Goldberg P., Andrew S. E., Theilmann J., Telenius H., Zeisler J., Squitieri F., Lin B., Bassett A., Almqvist E. A worldwide study of the Huntington's disease mutation. The sensitivity and specificity of measuring CAG repeats. N Engl J Med. 1994 May 19;330(20):1401–1406. doi: 10.1056/NEJM199405193302001. [DOI] [PubMed] [Google Scholar]
  18. Lucotte G., Gérard N., Roubertoux P., Schmitt I., Riess O. Relationships of the 2642 deletion polymorphism (delta 2642) in the huntingtin gene with the CAG repeat expansion length and age at onset of the disease. Genet Couns. 1996;7(4):297–302. [PubMed] [Google Scholar]
  19. MacMillan J. C., Snell R. G., Tyler A., Houlihan G. D., Fenton I., Cheadle J. P., Lazarou L. P., Shaw D. J., Harper P. S. Molecular analysis and clinical correlations of the Huntington's disease mutation. Lancet. 1993 Oct 16;342(8877):954–958. doi: 10.1016/0140-6736(93)92002-b. [DOI] [PubMed] [Google Scholar]
  20. Novelletto A., Persichetti F., Sabbadini G., Mandich P., Bellone E., Ajmar F., Squitieri F., Campanella G., Bozza A., MacDonald M. E. Polymorphism analysis of the huntingtin gene in Italian families affected with Huntington disease. Hum Mol Genet. 1994 Jul;3(7):1129–1132. doi: 10.1093/hmg/3.7.1129. [DOI] [PubMed] [Google Scholar]
  21. Roos R. A., Hermans J., Vegter-van der Vlis M., van Ommen G. J., Bruyn G. W. Duration of illness in Huntington's disease is not related to age at onset. J Neurol Neurosurg Psychiatry. 1993 Jan;56(1):98–100. doi: 10.1136/jnnp.56.1.98. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Rubinsztein D. C., Barton D. E., Davison B. C., Ferguson-Smith M. A. Analysis of the huntingtin gene reveals a trinucleotide-length polymorphism in the region of the gene that contains two CCG-rich stretches and a correlation between decreased age of onset of Huntington's disease and CAG repeat number. Hum Mol Genet. 1993 Oct;2(10):1713–1715. doi: 10.1093/hmg/2.10.1713. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Squitieri F., Andrew S. E., Goldberg Y. P., Kremer B., Spence N., Zeisler J., Nichol K., Theilmann J., Greenberg J., Goto J. DNA haplotype analysis of Huntington disease reveals clues to the origins and mechanisms of CAG expansion and reasons for geographic variations of prevalence. Hum Mol Genet. 1994 Dec;3(12):2103–2114. doi: 10.1093/hmg/3.12.2103. [DOI] [PubMed] [Google Scholar]
  25. Stine O. C., Pleasant N., Franz M. L., Abbott M. H., Folstein S. E., Ross C. A. Correlation between the onset age of Huntington's disease and length of the trinucleotide repeat in IT-15. Hum Mol Genet. 1993 Oct;2(10):1547–1549. doi: 10.1093/hmg/2.10.1547. [DOI] [PubMed] [Google Scholar]
  26. Telenius H., Kremer H. P., Theilmann J., Andrew S. E., Almqvist E., Anvret M., Greenberg C., Greenberg J., Lucotte G., Squitieri F. Molecular analysis of juvenile Huntington disease: the major influence on (CAG)n repeat length is the sex of the affected parent. Hum Mol Genet. 1993 Oct;2(10):1535–1540. doi: 10.1093/hmg/2.10.1535. [DOI] [PubMed] [Google Scholar]
  27. Warner J. P., Barron L. H., Brock D. J. 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. doi: 10.1006/mcpr.1993.1034. [DOI] [PubMed] [Google Scholar]
  28. Weigell-Weber M., Schmid W., Spiegel R. Psychiatric symptoms and CAG expansion in Huntington's disease. Am J Med Genet. 1996 Feb 16;67(1):53–57. doi: 10.1002/(SICI)1096-8628(19960216)67:1<53::AID-AJMG9>3.0.CO;2-T. [DOI] [PubMed] [Google Scholar]
  29. Zappacosta B., Monza D., Meoni C., Austoni L., Soliveri P., Gellera C., Alberti R., Mantero M., Penati G., Caraceni T. Psychiatric symptoms do not correlate with cognitive decline, motor symptoms, or CAG repeat length in Huntington's disease. Arch Neurol. 1996 Jun;53(6):493–497. doi: 10.1001/archneur.1996.00550060035012. [DOI] [PubMed] [Google Scholar]

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