Abstract
Direct molecular genetic testing carried out in 59 Huntington's disease patients belonging to 46 families from Bashkortostan revealed the (CAG) n repeat expansion in exon 1 of the IT15 gene in 57 of them. By use of this analysis the disease status was not confirmed in two patients with atypical form of the disease and negative family history. The (CAG) n repeat expansion was identified in 27 out of 127 asymptomatic at-risk individuals. Analysis of the mutant (CAG) n allele inheritance demonstrated extremely high instability and high mutation rate predominantly leading to the appearance of the alleles with increasing number of (CAG) n repeats in subsequent generations. The instability was mostly observed in cases of paternal transmission. Almost complete linkage disequilibrium between the (CCG)7 mutant alleles and the del2642 deletion was demonstrated. Three major haplotypes revealed, (CCG)7/del–, (CCG)7/del+, and (CCG)10/del–, implied the existence of at least three sources of the origin of Huntington's disease in Bashkortostan. The identified haplotype frequency distribution patterns displayed similarities with those in European populations. The contribution of a number of genetic factors to the age of onset of Huntington's disease was analyzed.
Similar content being viewed by others
REFERENCES
Hayden, M.R., Huntington’s Chorea, Berlin: Springer-Verlag, 1981.
Pridmore, S.A., The Prevalence of Huntington’s Disease in Tasmania, Med. J. Aust., 1990, vol. 6, pp. 133-134.
Leung, C.M., Chan, Y.W., Chang, C.M., et al., Huntington’s Disease in Chinese: A Hypothesis of Its Origin, J. Neurol. Neurosurg. Psychiatry, 1992, vol. 55, pp. 681-684.
Gusella, J.F., Wexler, N.S., Conneally, P.M., et al., A Polymorphic DNA Marker Genetically Linked to Huntington’s Disease, Nature, 1983, vol. 306, pp. 234-238.
Huntington’s Disease Collaborative Research Group, A Novel Gene Containing a Trinucleotide Repeat That Is Expanded and Unstable on Huntington’s Disease Chromosomes, Cell (Cambridge, Mass.), 1993, vol. 72, pp. 971-983.
Andrew, S.E., Goldberg, Y.P., Kremer, B., et al., The Relationship between Trinucleotide (CAG) Repeat Length and Clinical Features of Huntington’s Disease, Nat. Genet., 1993, vol. 4, pp. 398-403.
Mathew, C.C., The Isolation of High-Molecular-Weight Eukaryotic DNA, Methods in Molecular Biology, vol. 2, Walker, J.M., Ed., Clifton, New York: Human, 1984, pp. 31-34.
Malysheva, O.V., Molecular Genetic Analysis of the IT15and DMPKGenes in Populations and Families with Myotonic Dystrophy and Huntington’s Disease, Cand. Sci. (Biol.) Dissertation, St. Petersburg, 2000.
Goldberg, Y.P., Andrew, S.E., Clarke, L.A., and Hayden, M.R., A PCR Method for Accurate Assessment of Trinucleotide Repeat Expansion in Huntington Disease, Hum. Mol. Genet., 1993, vol. 2, no. 6, pp. 635-636.
Rubinsztein, D.C., Barton, D.E., Davison, B.C., and Ferguson-Smith, M.A., Analysis of 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, vol. 2, pp. 1713-1715.
Warner, J.P., Barron, L.H., and Brock, D.J.H., A New PCR Assay for the Trinucleotide Repeat That Is Unstable and Expanded on Huntington’s Disease Chromosomes, Mol. Cell. Probes, 1993, vol. 7, pp. 235-239.
StatSoft, STATISTICA for Windows (Computer Program Manual), Tulsa, OK: StatSoft, 1999; http://www.statsoft.com.
Shaw, M. and Caro, A., The Mutation Rate to Huntington’s Chorea, J. Med. Genet., 1982, vol. 19, p. 161.
MacDonald, M.E., Noveletto, A., Lin, C., et al., The Huntington’s Disease Candidate Region Exhibits Many Different Haplotypes, Nat. Genet., 1992, vol. 1, pp. 99-103.
Squitieri, F., Andrew, S.E., Goldberg, Y.P., et al., DNA Haplotype Analysis of Huntington Disease Reveals Clues to the Origins and Mechanisms of CAG Expansion and Reasons for Geographic Variation of Prevalence, Hum. Mol. Genet., 1994, vol. 3, pp. 2103-2114.
Illarioshkin, S.N., Ivanova-Smolenskaya, I.A., Markova, E.D., et al., Analysis of Trinucleotide Repeat Expansion as a New Mechanism of Mutation in Huntington’s Chorea: Theoretical and Applied Aspects, Genetika (Moscow), 1996, vol. 32, no. 1, pp. 103-109.
Duyao, M., Ambrose, C., Myers, R., et al., Trinucleotide Repeat Length Instability and Age of Onset in Huntington’s Disease, Nat. Genet., 1993, vol. 4, pp. 387-392.
Kremer, B., Squitieri, F., Telenius, H., et al., Molecular Analysis of Late-Onset Huntington’s Disease, J. Med. Genet., 1993, vol. 30, pp. 991-995.
Atac, F.B., Elibol, B., and Schaefer, F., The Genetic Analysis of Turkish Patients with Huntington’s Disease, Acta Neurol. Scand., 1999, vol. 100, pp. 195-198.
Lucotte, G., Gerard, N., Roubertoux, P., et al., Relationships of the 2642 Deletion Polymorphism (delta2642) in the Huntingtin Gene with the CAG Repeat Expansion Length and Age at Onset of the Disease, Genet. Couns., 1996, vol. 7, pp. 297-302.
Vuillaume, I., Vermersch, P., Destee, A., et al., Genetic Polymorphisms Adjacent to the CAG Repeat Influence Clinical Features at Onset in Huntington’s Disease, J. Neurol. Neurosurg. Psychiatry, 1998, vol. 64, pp. 758-762.
Noveletto, A., Persichetti, F., Sabbadini, G., et al., Polymorphism Analysis of Huntingtin Gene in Italian Families Affected with Huntington Disease, Hum. Mol. Genet., 1994, vol. 3, pp. 1129-1132.
Kehoe, P., Krawczak, M., Harper, P.S., et al., Age of Onset in Huntington Disease: Sex-Specific Influence of Apolipoprotein E Genotype and Normal CAG Repeat Length, J. Med. Genet., 1999, vol. 36, pp. 108-111.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kutuev, I.A., Khusainova, R.I., Khidiyatova, I.M. et al. Analysis of the IT15 Gene in Huntington's Disease Families. Russian Journal of Genetics 40, 919–925 (2004). https://doi.org/10.1023/B:RUGE.0000039726.96053.78
Issue Date:
DOI: https://doi.org/10.1023/B:RUGE.0000039726.96053.78