1. Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers
- Author
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Rosa Rademakers, Andrew Kertesz, Kimmo J. Hatanpaa, Melissa E. Murray, Michael J. Strong, Neill R. Graff-Radford, Elizabeth Finger, Richard J. Caselli, Ian R. Mackenzie, Kevin B. Boylan, Anna Karydas, Joseph E. Parisi, Manuela Neumann, Thomas G. Beach, David S. Knopman, Bradley F. Boeve, Keith A. Josephs, Bianca Mullen, Ging-Yuek Robin Hsiung, Ronald C. Petersen, Lea T. Grinberg, William W. Seeley, Sandra Weintraub, Michael G. Heckman, Heather Stewart, Matt Baker, Eileen H. Bigio, Zbigniew K. Wszolek, Carol F. Lippa, Marka van Blitterswijk, Charles L. White, Dennis W. Dickson, Leonard Petrucelli, M.-Marsel Mesulam, Patricia H. Brown, Bruce L. Miller, and Mariely DeJesus-Hernandez
- Subjects
Male ,Aging ,SMN1 ,Neurodegenerative ,Cohort Studies ,SMN2 protein, human ,genetics [Survival of Motor Neuron 2 Protein] ,C9orf72 ,Amyotrophic lateral sclerosis ,genetics [Frontotemporal Dementia] ,genetics [Nerve Tissue Proteins] ,NIPA1 protein, human ,Ataxin-2 ,Genetics ,DNA Repeat Expansion ,General Neuroscience ,ATXN2 ,genetics [Survival of Motor Neuron 1 Protein] ,Middle Aged ,Disease modifier ,Survival of Motor Neuron 2 Protein ,genetics [Membrane Proteins] ,Frontotemporal Dementia (FTD) ,Ataxins ,Frontotemporal Dementia ,Neurological ,genetics [Motor Neuron Disease] ,Frontotemporal dementia ,Adult ,Heterozygote ,Clinical Sciences ,genetics [DNA Repeat Expansion] ,C9ORF72 ,Nerve Tissue Proteins ,Biology ,Article ,Rare Diseases ,Clinical Research ,Angelman syndrome ,medicine ,Acquired Cognitive Impairment ,Humans ,ddc:610 ,Motor neuron disease ,Motor Neuron Disease ,Genetic Association Studies ,Neurology & Neurosurgery ,C9orf72 Protein ,Genetic heterogeneity ,Neurosciences ,Proteins ,Membrane Proteins ,medicine.disease ,genetics [Proteins] ,Survival of Motor Neuron 1 Protein ,nervous system diseases ,Brain Disorders ,Ataxin ,Dementia ,Human medicine ,Neurology (clinical) ,C9orf72 protein, human ,SMN1 protein, human ,Geriatrics and Gerontology ,ALS ,Developmental Biology - 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. (C) 2014 Elsevier Inc. All rights reserved.
- Published
- 2014
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