Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers

NEUROBIOLOGY OF AGING

卷:35

Article

Van Blitterswijk, Marka¹  Mullen, Bianca¹  Heckman, Michael G.²  Baker, Matthew C.¹  DeJesus-Hernandez, Mariely¹  Brown, Patricia H.¹  Murray, Melissa E.¹  Hsiung, Ging-Yuek R.³  Stewart, Heather³  Karydas, Anna M.⁴  Finger, Elizabeth⁵  Kertesz, Andrew⁵  Bigio, Eileen H.⁶  Weintraub, Sandra⁶  Mesulam, Marsel⁶  Hatanpaa, Kimmo J.⁷  White, Charles L., III⁷  Neumann, Manuela⁸  Strong, Michael J.⁹  Beach, Thomas G.¹⁰  Wszolek, Zbigniew K.¹¹  Lippa, Carol¹²  Caselli, Richard¹³  Petrucelli, Leonard¹  Josephs, Keith A.¹⁴  Parisi, Joseph E.¹⁴  Knopman, David S.¹⁴  Petersen, Ronald C.¹⁴  Mackenzie, Ian R.¹⁵  Seeley, William W.⁴  Grinberg, Lea T.⁴  Miller, Bruce L.⁴  Boylan, Kevin B.¹¹  Graff-Radford, Neill R.¹¹  Boeve, Bradley F.¹⁴  Dickson, Dennis W.¹  Rademakers, Rosa¹ 

[1] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

[2] Mayo Clin, Biostat Sect, Jacksonville, FL 32224 USA

[3] Univ British Columbia, Div Neurol, Vancouver, BC V5Z 1M9, Canada

[4] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA

[5] Univ Western Ontario, Schulich Sch Med & Dent, Dept Clin Neurol Sci, London, ON, Canada

[6] NW Univ Feinberg, Sch Med, Cognit Neurol & Alzheimers Dis Ctr, Chicago, IL USA

[7] Univ Texas SW Med Ctr Dallas, Dept Pathol & Alzheimers Dis Ctr, Dallas, TX 75390 USA

[8] Univ Tubingen, German Ctr Neurodegenerat Dis, Dept Neuropathol, Tubingen, Germany

[9] Robarts Res Inst, Mol Brain Res Grp, London, ON N6A 5C1, Canada

[10] Banner Sun Hlth Res Inst, Civin Lab Neuropathol, Sun City, AZ USA

[11] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA

[12] Drexel Univ, Coll Med, Dept Neurol, Philadelphia, PA 19104 USA

[13] Mayo Clin, Dept Neurol, Phoenix, AZ USA

[14] Mayo Clin, Dept Neurol, Rochester, MN USA

[15] Univ British Columbia, Dept Pathol, Lab Med, Vancouver, BC, Canada

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

DOI  :  10.1016/j.neurobiolaging.2014.04.016

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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