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. Beach; Zbigniew 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

doi:10.1016/j.neurobiolaging.2014.04.016

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Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers

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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, …

Neurobiology of aging, v 35(10), pp 2421.e13-2421.e17

Oct 2014

DOI: https://doi.org/10.1016/j.neurobiolaging.2014.04.016

PMID: 24866401

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Abstract

Amyotrophic lateral sclerosis

Ataxin-2

ATXN2

C9ORF72

Disease modifier

Frontotemporal dementia

Motor neuron disease

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.

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Title: Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers
Creators: Marka van Blitterswijk - Mayo Clinic
Bianca Mullen - Mayo Clinic
Michael G. Heckman - Mayo Clinic
Matthew C. Baker - Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
Mariely DeJesus-Hernandez - Mayo Clinic
Patricia H. Brown - Mayo Clinic
Melissa E. Murray - Mayo Clinic
Ging-Yuek R. Hsiung - University of British Columbia
Heather Stewart - University of British Columbia
Anna M. Karydas - University of California, San Francisco
Elizabeth Finger - Western University
Andrew Kertesz - Western University
Eileen H. Bigio - Northwestern University
Sandra Weintraub - Northwestern University
Marsel Mesulam - Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Kimmo J. Hatanpaa - The University of Texas Southwestern Medical Center
Charles L. White - The University of Texas Southwestern Medical Center
Manuela Neumann - German Center for Neurodegenerative Diseases
Michael J. Strong - Western University
Thomas G. Beach - Banner Sun Health Research Institute
Zbigniew K. Wszolek - Mayo Clinic
Carol Lippa - Drexel University
Richard Caselli - Department of Neurology; Mayo Clinic; Phoenix AZ USA
Leonard Petrucelli - Mayo Clinic
Keith A. Josephs - Mayo Clinic
Joseph E. Parisi - Mayo Clinic
David S. Knopman - Mayo Clinic
Ronald C. Petersen - Mayo Clinic
Ian R. Mackenzie - University of British Columbia
William W. Seeley - University of California, San Francisco
Lea T. Grinberg - University of California, San Francisco
Bruce L. Miller - University of California, San Francisco
Kevin B. Boylan - Mayo Clinic
Neill R. Graff-Radford - Mayo Clinic
Bradley F. Boeve - Mayo Clinic
Dennis W. Dickson - Mayo Clinic
Rosa Rademakers - Mayo Clinic
Publication Details: Neurobiology of aging, v 35(10), pp 2421.e13-2421.e17
Publisher: Elsevier
Resource Type: Journal article
Language: English
Web of Science ID: WOS:000339735100034
Scopus ID: 2-s2.0-84903819005
Other Identifier: 991019312444504721

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Collaboration types: Domestic collaboration; International collaboration
Web of Science research areas: Geriatrics & Gerontology; Neurosciences

Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers

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