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Neurobiol Aging. 2014 Oct;35(10):2421.e13-7. doi: 10.1016/j.neurobiolaging.2014.04.016. Epub 2014 May 2.

Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers.

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  • 1Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
  • 2Section of Biostatistics, Mayo Clinic, Jacksonville, FL, USA.
  • 3Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada.
  • 4Department of Neurology, University of California, San Francisco, CA, USA.
  • 5Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada.
  • 6Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 7Department of Pathology and Alzheimer's Disease Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 8Department of Neuropathology, University of Tübingen and German Center for Neurodegenerative Diseases, Tübingen, Germany.
  • 9Molecular Brain Research Group, Robarts Research Institute, London, Ontario, Canada.
  • 10Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
  • 11Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
  • 12Department of Neurology, Drexel University College of Medicine, Philadelphia, PA, USA.
  • 13Department of Neurology, Mayo Clinic, Phoenix, AZ, USA.
  • 14Department of Neurology, Mayo Clinic, Rochester, MN, USA.
  • 15Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
  • 16Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. Electronic address:


Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are an important cause of both motor neuron disease (MND) and frontotemporal dementia (FTD). Currently, little is known about factors that could account for the phenotypic heterogeneity detected in C9ORF72 expansion carriers. In this study, we investigated 4 genes that could represent genetic modifiers: ataxin-2 (ATXN2), non-imprinted in Prader-Willi/Angelman syndrome 1 (NIPA1), survival motor neuron 1 (SMN1), and survival motor neuron 2 (SMN2). Assessment of these genes, in a unique cohort of 331 C9ORF72 expansion carriers and 376 control subjects, revealed that intermediate repeat lengths in ATXN2 possibly act as disease modifier in C9ORF72 expansion carriers; no evidence was provided for a potential role of NIPA1, SMN1, or SMN2. The effects of intermediate ATXN2 repeats were most profound in probands with MND or FTD/MND (2.1% vs. 0% in control subjects, p = 0.013), whereas the frequency in probands with FTD was identical to control subjects. Though intermediate ATXN2 repeats were already known to be associated with MND risk, previous reports did not focus on individuals with clear pathogenic mutations, such as repeat expansions in C9ORF72. Based on our present findings, we postulate that intermediate ATXN2 repeat lengths may render C9ORF72 expansion carriers more susceptible to the development of MND; further studies are needed, however, to validate our findings.

Copyright © 2014 Elsevier Inc. All rights reserved.


ATXN2; Amyotrophic lateral sclerosis; Ataxin-2; C9ORF72; Disease modifier; Frontotemporal dementia; Motor neuron disease

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