title: Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers.
abstract: 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.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Marka
authors.initials: M
authors.lastname: van Blitterswijk
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Bianca
authors.initials: B
authors.lastname: Mullen
authors.affiliation: Section of Biostatistics, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Heckman
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Baker
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Mariely
authors.initials: M
authors.lastname: DeJesus-Hernandez
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Brown
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Murray
authors.affiliation: Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ging-Yuek R
authors.initials: GY
authors.lastname: Hsiung
authors.affiliation: Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Heather
authors.initials: H
authors.lastname: Stewart
authors.affiliation: Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Karydas
authors.affiliation: Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Finger
authors.affiliation: Department of Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kertesz
authors.affiliation: Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Eileen H
authors.initials: EH
authors.lastname: Bigio
authors.affiliation: Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Weintraub
authors.affiliation: Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Marsel
authors.initials: M
authors.lastname: Mesulam
authors.affiliation: Department of Pathology and Alzheimer's Disease Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Kimmo J
authors.initials: KJ
authors.lastname: Hatanpaa
authors.affiliation: Department of Pathology and Alzheimer's Disease Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Charles L
authors.initials: CL
authors.lastname: White
authors.affiliation: Department of Neuropathology, University of Tübingen and German Center for Neurodegenerative Diseases, Tübingen, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
authors.affiliation: Molecular Brain Research Group, Robarts Research Institute, London, Ontario, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Strong
authors.affiliation: Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.affiliation: Department of Neurology, Drexel University College of Medicine, Philadelphia, PA, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Lippa
authors.affiliation: Department of Neurology, Mayo Clinic, Phoenix, AZ, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Caselli
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Josephs
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Knopman
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mackenzie
authors.affiliation: Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.affiliation: Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Lea T
authors.initials: LT
authors.lastname: Grinberg
authors.affiliation: Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Boylan
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. Electronic address: Rademakers.Rosa@mayo.edu.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
mesh_terms: D000328:Adult; D000067528:Ataxins; D000073885:C9orf72 Protein; D015331:Cohort Studies; D042622:DNA Repeat Expansion / Q000235:genetics*; D057180:Frontotemporal Dementia / Q000235:genetics; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics
chemical_list: D000067528:Ataxins; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D008565:Membrane Proteins; C478824:NIPA1 protein, human; D009419:Nerve Tissue Proteins; D011506:Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein
keywords: ATXN2; Amyotrophic lateral sclerosis; Ataxin-2; C9ORF72; Disease modifier; Frontotemporal dementia; Motor neuron disease