Ataxin-2 repeat-length variation and neurodegeneration (original) (raw)

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Department of Neuroscience

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Department of Neuroscience

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Department of Neuroscience

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Alexandra I. Soto-Ortolaza

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Department of Neuroscience

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Department of Neuroscience

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Mariely DeJesus-Hernandez

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Department of Neuroscience

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Department of Neuroscience

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Department of Neuroscience

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Department of Neurology

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Mayo Clinic

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Jacksonville, FL

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USA,

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Molecular Brain Research Group

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Robarts Research Institute

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London, Ontario

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Canada

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Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry

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The University of Western Ontario

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London, Ontario

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Canada

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Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry

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The University of Western Ontario

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London, Ontario

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Revision received:

07 May 2011

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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 Gerpen, James 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 C. Petersen, Zbigniew K. Wszolek, Dennis W. Dickson, Rosa Rademakers, Ataxin-2 repeat-length variation and neurodegeneration, Human Molecular Genetics, Volume 20, Issue 16, 15 August 2011, Pages 3207–3212, https://doi.org/10.1093/hmg/ddr227
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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 = 5.57; _P_= 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR = 5.83; _P_= 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.

© The Author 2011. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Topic:

• alleles
• phenotype
• parkinson disease
• alzheimer's disease
• amyotrophic lateral sclerosis
• nerve degeneration
• neurodegenerative disorders
• progressive supranuclear palsy
• glutamine
• rna
• spinocerebellar ataxia type 2
• genetic risk
• frontotemporal lobar degeneration
• protein tdp-43

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