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 John Caselli, Leonard Petrucelli, Keith Anthony Josephs, Joseph E Parisi, David S Knopman, Ronald Carl 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 V Rademakers

Research output: Contribution to journalArticle

52 Citations (Scopus)

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.

Original languageEnglish (US)
JournalNeurobiology of Aging
Volume35
Issue number10
DOIs
StatePublished - 2014

Fingerprint

Chromosomes, Human, Pair 9
Open Reading Frames
Motor Neuron Disease
Motor Neurons
Angelman Syndrome
Prader-Willi Syndrome
Frontotemporal Dementia
Genes
Ataxin-2
Mutation

Keywords

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

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers. / Van Blitterswijk, Marka; Mullen, Bianca; Heckman, Michael G.; Baker, Matthew C.; DeJesus-Hernandez, Mariely; Brown, Patricia H.; Murray, Melissa E; Hsiung, Ging Yuek R; Stewart, Heather; Karydas, Anna M.; Finger, Elizabeth; Kertesz, Andrew; Bigio, Eileen H.; Weintraub, Sandra; Mesulam, Marsel; Hatanpaa, Kimmo J.; White, Charles L.; Neumann, Manuela; Strong, Michael J.; Beach, Thomas G.; Wszolek, Zbigniew K; Lippa, Carol; Caselli, Richard John; Petrucelli, Leonard; Josephs, Keith Anthony; Parisi, Joseph E; Knopman, David S; Petersen, Ronald Carl; Mackenzie, Ian R.; Seeley, William W.; Grinberg, Lea T.; Miller, Bruce L.; Boylan, Kevin B.; Graff Radford, Neill R; Boeve, Bradley F; Dickson, Dennis W; Rademakers, Rosa V.

In: Neurobiology of Aging, Vol. 35, No. 10, 2014.

Research output: Contribution to journalArticle

Van Blitterswijk, M, Mullen, B, Heckman, MG, Baker, MC, DeJesus-Hernandez, M, Brown, PH, Murray, ME, Hsiung, GYR, Stewart, H, Karydas, AM, Finger, E, Kertesz, A, Bigio, EH, Weintraub, S, Mesulam, M, Hatanpaa, KJ, White, CL, Neumann, M, Strong, MJ, Beach, TG, Wszolek, ZK, Lippa, C, Caselli, RJ, Petrucelli, L, Josephs, KA, Parisi, JE, Knopman, DS, Petersen, RC, Mackenzie, IR, Seeley, WW, Grinberg, LT, Miller, BL, Boylan, KB, Graff Radford, NR, Boeve, BF, Dickson, DW & Rademakers, RV 2014, 'Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers', Neurobiology of Aging, vol. 35, no. 10. https://doi.org/10.1016/j.neurobiolaging.2014.04.016
Van Blitterswijk, Marka ; Mullen, Bianca ; Heckman, Michael G. ; Baker, Matthew C. ; DeJesus-Hernandez, Mariely ; Brown, Patricia H. ; Murray, Melissa E ; Hsiung, Ging Yuek R ; Stewart, Heather ; Karydas, Anna M. ; Finger, Elizabeth ; Kertesz, Andrew ; Bigio, Eileen H. ; Weintraub, Sandra ; Mesulam, Marsel ; Hatanpaa, Kimmo J. ; White, Charles L. ; Neumann, Manuela ; Strong, Michael J. ; Beach, Thomas G. ; Wszolek, Zbigniew K ; Lippa, Carol ; Caselli, Richard John ; Petrucelli, Leonard ; Josephs, Keith Anthony ; Parisi, Joseph E ; Knopman, David S ; Petersen, Ronald Carl ; Mackenzie, Ian R. ; Seeley, William W. ; Grinberg, Lea T. ; Miller, Bruce L. ; Boylan, Kevin B. ; Graff Radford, Neill R ; Boeve, Bradley F ; Dickson, Dennis W ; Rademakers, Rosa V. / Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers. In: Neurobiology of Aging. 2014 ; Vol. 35, No. 10.
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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.",
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T1 - Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers

AU - Van Blitterswijk, Marka

AU - Mullen, Bianca

AU - Heckman, Michael G.

AU - Baker, Matthew C.

AU - DeJesus-Hernandez, Mariely

AU - Brown, Patricia H.

AU - Murray, Melissa E

AU - Hsiung, Ging Yuek R

AU - Stewart, Heather

AU - Karydas, Anna M.

AU - Finger, Elizabeth

AU - Kertesz, Andrew

AU - Bigio, Eileen H.

AU - Weintraub, Sandra

AU - Mesulam, Marsel

AU - Hatanpaa, Kimmo J.

AU - White, Charles L.

AU - Neumann, Manuela

AU - Strong, Michael J.

AU - Beach, Thomas G.

AU - Wszolek, Zbigniew K

AU - Lippa, Carol

AU - Caselli, Richard John

AU - Petrucelli, Leonard

AU - Josephs, Keith Anthony

AU - Parisi, Joseph E

AU - Knopman, David S

AU - Petersen, Ronald Carl

AU - Mackenzie, Ian R.

AU - Seeley, William W.

AU - Grinberg, Lea T.

AU - Miller, Bruce L.

AU - Boylan, Kevin B.

AU - Graff Radford, Neill R

AU - Boeve, Bradley F

AU - Dickson, Dennis W

AU - Rademakers, Rosa V

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Amyotrophic lateral sclerosis

KW - Ataxin-2

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KW - C9ORF72

KW - Disease modifier

KW - Frontotemporal dementia

KW - Motor neuron disease

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