Ataxin-2 repeat-length variation and neurodegeneration

Owen A Ross, Nicola J. Rutherford, Matt Baker, Alexandra I. Soto-Ortolaza, Minerva M Carrasquillo, Mariely DeJesus-Hernandez, Jennifer Adamson, Ma Li, Kathryn Volkening, Elizabeth Finger, William W. Seeley, Kimmo J. Hatanpaa, Catherine Lomen-Hoerth, Andrew Kertesz, Eileen H. Bigio, Carol Lippa, Bryan K Woodruff, David S Knopman, Charles L. White, Jay A Van GerpenJames F Meschia, Ian R. Mackenzie, Kevin Boylan, Bradley F Boeve, Bruce L. Miller, Michael J. Strong, Ryan J. Uitti, Steven G Younkin, Neill R Graff Radford, Ronald Carl Petersen, Zbigniew K Wszolek, Dennis W Dickson, Rosa V Rademakers

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR 5 5.57; P 5 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR 5 5.83; P 5 0.004; repeat length >30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31-33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.

Original languageEnglish (US)
Article numberddr227
Pages (from-to)3207-3212
Number of pages6
JournalHuman Molecular Genetics
Volume20
Issue number16
DOIs
StatePublished - Aug 2011

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Neurodegenerative Diseases
Amyotrophic Lateral Sclerosis
Progressive Supranuclear Palsy
Spinocerebellar Ataxias
Frontotemporal Lobar Degeneration
Ataxin-2
Glutamine
Parkinson Disease
Alzheimer Disease
Logistic Models
Alleles
Regression Analysis
RNA
Phenotype

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Ross, O. A., Rutherford, N. J., Baker, M., Soto-Ortolaza, A. I., Carrasquillo, M. M., DeJesus-Hernandez, M., ... Rademakers, R. V. (2011). Ataxin-2 repeat-length variation and neurodegeneration. Human Molecular Genetics, 20(16), 3207-3212. [ddr227]. https://doi.org/10.1093/hmg/ddr227

Ataxin-2 repeat-length variation and neurodegeneration. / Ross, Owen A; Rutherford, Nicola J.; Baker, Matt; Soto-Ortolaza, Alexandra I.; Carrasquillo, Minerva M; DeJesus-Hernandez, Mariely; Adamson, Jennifer; Li, Ma; Volkening, Kathryn; Finger, Elizabeth; Seeley, William W.; Hatanpaa, Kimmo J.; Lomen-Hoerth, Catherine; Kertesz, Andrew; Bigio, Eileen H.; Lippa, Carol; Woodruff, Bryan K; Knopman, David S; White, Charles L.; Van Gerpen, Jay A; Meschia, James F; Mackenzie, Ian R.; Boylan, Kevin; Boeve, Bradley F; Miller, Bruce L.; Strong, Michael J.; Uitti, Ryan J.; Younkin, Steven G; Graff Radford, Neill R; Petersen, Ronald Carl; Wszolek, Zbigniew K; Dickson, Dennis W; Rademakers, Rosa V.

In: Human Molecular Genetics, Vol. 20, No. 16, ddr227, 08.2011, p. 3207-3212.

Research output: Contribution to journalArticle

Ross, OA, Rutherford, NJ, Baker, M, Soto-Ortolaza, AI, Carrasquillo, MM, DeJesus-Hernandez, M, Adamson, J, Li, M, Volkening, K, Finger, E, Seeley, WW, Hatanpaa, KJ, Lomen-Hoerth, C, Kertesz, A, Bigio, EH, Lippa, C, Woodruff, BK, Knopman, DS, White, CL, Van Gerpen, JA, Meschia, JF, Mackenzie, IR, Boylan, K, Boeve, BF, Miller, BL, Strong, MJ, Uitti, RJ, Younkin, SG, Graff Radford, NR, Petersen, RC, Wszolek, ZK, Dickson, DW & Rademakers, RV 2011, 'Ataxin-2 repeat-length variation and neurodegeneration', Human Molecular Genetics, vol. 20, no. 16, ddr227, pp. 3207-3212. https://doi.org/10.1093/hmg/ddr227
Ross OA, Rutherford NJ, Baker M, Soto-Ortolaza AI, Carrasquillo MM, DeJesus-Hernandez M et al. Ataxin-2 repeat-length variation and neurodegeneration. Human Molecular Genetics. 2011 Aug;20(16):3207-3212. ddr227. https://doi.org/10.1093/hmg/ddr227
Ross, Owen A ; Rutherford, Nicola J. ; Baker, Matt ; Soto-Ortolaza, Alexandra I. ; Carrasquillo, Minerva M ; DeJesus-Hernandez, Mariely ; Adamson, Jennifer ; Li, Ma ; Volkening, Kathryn ; Finger, Elizabeth ; Seeley, William W. ; Hatanpaa, Kimmo J. ; Lomen-Hoerth, Catherine ; Kertesz, Andrew ; Bigio, Eileen H. ; Lippa, Carol ; Woodruff, Bryan K ; Knopman, David S ; White, Charles L. ; Van Gerpen, Jay A ; Meschia, James F ; Mackenzie, Ian R. ; Boylan, Kevin ; Boeve, Bradley F ; Miller, Bruce L. ; Strong, Michael J. ; Uitti, Ryan J. ; Younkin, Steven G ; Graff Radford, Neill R ; Petersen, Ronald Carl ; Wszolek, Zbigniew K ; Dickson, Dennis W ; Rademakers, Rosa V. / Ataxin-2 repeat-length variation and neurodegeneration. In: Human Molecular Genetics. 2011 ; Vol. 20, No. 16. pp. 3207-3212.
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