Author:
Che Hong Van B,Metzger Silke,Portal Esteban,Deyle Carolin,Riess Olaf,Nguyen Huu Phuc
Abstract
Abstract
Background
Huntington disease (HD) is caused by a polyglutamine expansion of more than 35 units in the huntingtin protein. This expanded repeat length inversely correlates with the age-at-onset (AAO), however, additional genetic factors apart from the expanded CAG repeat size are thought to influence the course and the AAO in HD. Until now, among others, the gene encoding PCG-1α (PPARGC1A) was shown to modify the AAO in two independent, however small, populations. PGC-1α is involved in the induction of various mechanisms regulating mitochondrial biogenesis and oxidative stress defence. Furthermore, several studies have linked impairment of its function and/or its expression to HD pathogenesis. As the identification of distinct modifiers in association studies is largely dependent on the size of the observed population, we investigated nine different single nucleotide polymorphisms (SNPs) in PPARGC1A in order to replicate the disease modifying effect in more than 800 European HD patients and to identify an association with AAO in HD.
Results
Two SNPs, one in the promoter and one in the transcribed region of the gene, showed a significant effect on the AAO. While the minor allele of SNP rs7665116 (g.38570C), located in the transcribed gene region, was associated with a delay in disease onset, especially in HD patients with Italian ancestry, the minor allele of SNP rs2970870 (g.-1437C) in the promoter region leads to an earlier onset of HD in its homozygous state. Additionally, global testing of haplotype block 2, which covers the main part of the transcribed region of the gene, revealed an association between block 2 haplotypes and the disease onset.
Conclusion
Therefore, our results indicate opposing modifying influences of two SNPs within one gene on AAO and support the idea that PGC-1α dysfunction is involved in HD pathology.
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Clinical Neurology,Molecular Biology
Reference38 articles.
1. Group THsDCR: A novel gene containing a trinucleotide repeat that is unstable on Huntington's disease chromosomes. Cell. 1993, 26: 971-983.
2. Brinkman RR, Mezei MM, Theilmann J, Almqvist E, Hayden MR: The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. American journal of human genetics. 1997, 60 (5): 1202-1210.
3. Lucotte G, Turpin JC, Riess O, Epplen JT, Siedlaczk I, Loirat F, Hazout S: Confidence intervals for predicted age of onset, given the size of (CAG)n repeat, in Huntington's disease. Human genetics. 1995, 95 (2): 231-232. 10.1007/BF00209410.
4. Wexler NS, Lorimer J, Porter J, Gomez F, Moskowitz C, Shackell E, Marder K, Penchaszadeh G, Roberts SA, Gayan J, et al: Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset. Proceedings of the National Academy of Sciences of the United States of America. 2004, 101 (10): 3498-3503. 10.1073/pnas.0308679101.
5. Metzger S, Rong J, Nguyen HP, Cape A, Tomiuk J, Soehn AS, Propping P, Freudenberg-Hua Y, Freudenberg J, Tong L, et al: Huntingtin-associated protein-1 is a modifier of the age-at-onset of Huntington's disease. Human molecular genetics. 2008, 17 (8): 1137-1146. 10.1093/hmg/ddn003.
Cited by
65 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献