Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers

Marka van Blitterswijk, Bianca Mullen, Michael G. Heckman, Matthew C. Baker, Mariely DeJesus-Hernandez, Patricia H. Brown, Melissa E. Murray, Ging Yuek R. Hsiung, Heather Stewart, Anna M. Karydas, Elizabeth Finger, Andrew Kertesz, Eileen H. Bigio, Sandra Weintraub, Marsel Mesulam, Kimmo J. Hatanpaa, Charles L. White, Manuela Neumann, Michael J. Strong, Thomas G. BeachZbigniew K. Wszolek, Carol Lippa, Richard Caselli, Leonard Petrucelli, Keith A. Josephs, Joseph E. Parisi, David S. Knopman, Ronald C. Petersen, Ian R. Mackenzie, William W. Seeley, Lea T. Grinberg, Bruce L. Miller, Kevin B. Boylan, Neill R. Graff-Radford, Bradley F. Boeve, Dennis W. Dickson, Rosa Rademakers

Research output: Contribution to journalArticlepeer-review

65 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2421.e13-2421.e17
JournalNeurobiology of aging
Issue number10
StatePublished - Oct 2014


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

ASJC Scopus subject areas

  • General Neuroscience
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology


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