Ataxin-2 repeat-length variation and neurodegeneration.

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.

• Authors: 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 3rd, 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
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 20 Issue 16 Pg. 3207-12 (Aug 15 2011) ISSN: 1460-2083 [Electronic] England
• PMID: 21610160 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ataxins
• Nerve Tissue Proteins

Topics

• Adult
• Aged
• Aged, 80 and over
• Ataxins
• Cohort Studies
• Demography
• Female
• Humans
• Male
• Middle Aged
• Nerve Degeneration (genetics, pathology)
• Nerve Tissue Proteins (genetics)
• Repetitive Sequences, Nucleic Acid (genetics)
• Trinucleotide Repeat Expansion (genetics)