Ataxin-2 repeat-length variation and neurodegeneration

Owen A. Ross; Nicola J. Rutherford; Matt Baker; Alexandra I. Soto-Ortolaza; Minerva M. Carrasquillo; Mariely DeJesus-Hernandez; Jennifer Adamson; Ma Li; Kathryn Volkening; Elizabeth Finger; William W. Seeley; Kimmo J. Hatanpaa; Catherine Lomen-Hoerth; Andrew Kertesz; Eileen H. Bigio; Carol Lippa; Bryan K. Woodruff; David S. Knopman; Charles L. White; Jay A. Van Gerpen; James F. Meschia; Ian R. Mackenzie; Kevin Boylan; Bradley F. Boeve; Bruce L. Miller; Michael J. Strong; Ryan J. Uitti; Steven G. Younkin; Neill R. Graff-Radford; Ronald C. Petersen; Zbigniew K. Wszolek; Dennis W. Dickson; Rosa Rademakers

doi:10.1093/hmg/ddr227

Ataxin-2 repeat-length variation and neurodegeneration

Owen A. Ross, Nicola J. Rutherford, Matt Baker, Alexandra I. Soto-Ortolaza, Minerva M. Carrasquillo, Mariely DeJesus-Hernandez, Jennifer Adamson, Ma Li, Kathryn Volkening, Elizabeth Finger, William W. Seeley, Kimmo J. Hatanpaa, Catherine Lomen-Hoerth, Andrew Kertesz, Eileen H. Bigio, Carol Lippa, Bryan K. Woodruff, David S. Knopman, Charles L. White, Jay A. Van GerpenJames F. Meschia, Ian R. Mackenzie, Kevin Boylan, Bradley F. Boeve, Bruce L. Miller, Michael J. Strong, Ryan J. Uitti, Steven G. Younkin, Neill R. Graff-Radford, Ronald C. Petersen, Zbigniew K. Wszolek, Dennis W. Dickson, Rosa Rademakers^*

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

138 Scopus citations

Abstract

Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR 5 5.57; P 5 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR 5 5.83; P 5 0.004; repeat length >30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31-33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.

Original language	English (US)
Pages (from-to)	3207-3212
Number of pages	6
Journal	Human molecular genetics
Volume	20
Issue number	16
DOIs	https://doi.org/10.1093/hmg/ddr227
State	Published - Aug 2011

Funding

This work was supported by the National Institutes of Health [grant numbers R01 NS065782 P50 AG16574 (Mayo ADRC RCP PI; to R.R., B.F.B., N.R.G.-R., D.W.D., S.G.Y.), U01 AG06576 (Mayo Alzheimer’s Disease Patient Registry: RCP PI); R01 NS065782 (R.R.), R01 AG26251 (R.R.), R01 AG18023 (N.R.G.-R., S.G.Y.), AG1657303 (B.L.M., W.W.S.), AG25711 (D.W.D.), AG17216 (D.W.D.), AG03 949 (D.W.D.), AG13854 (E.H.B.), P30 AG19610 – 01 (Arizona Alzheimer’s Disease Consortium: B.K.W.)] and the Peebler PSP Research Foundation (R.R.) and the ALS association (R.R.). Mayo Clinic Jacksonville is a Morris K. Udall Parkinson’s Disease Research Center of Excellence supported by the NINDS [grant number P50 #NS072187]. Z.K.W. is also partially funded by the National Institutes of Health [grant numbers R01 NS057567 and 1RC2NS070276] and by Mayo Clinic Florida CR programs (MCF 90052018 and MCF 90052030). O.A.R., D.W.D., Z.K.W. and R.J.U. are supported by the family of Carl and Susan Bolch. K.J.H. and C.L.W. were supported by National Institutes of Health [grant number 5P30AG012300], the Winspear Family Center for Research on the Neuropathology of Alzheimer Disease and the McCune Foundation. I.R.M. was supported by the Canadian Institutes of Health Research Operating [#74580] and the Pacific Alzheimer’s Disease Research Foundation. This project was also generously supported by the Robert and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program (R.C.P., D.W.D., N.R.G.-R., S.G.Y.) and by the Palumbo Professorship in Alzheimer’s Disease Research (S.G.Y.). ISGS samples were collected under funding from National Institute of Neurological Disorders and Stroke [grant number R01 NS42733 (J.F.M.)].

ASJC Scopus subject areas

Genetics(clinical)
Genetics
Molecular Biology

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10.1093/hmg/ddr227

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Ross, O. A., Rutherford, N. J., Baker, M., Soto-Ortolaza, A. I., Carrasquillo, M. M., DeJesus-Hernandez, M., Adamson, J., Li, M., Volkening, K., Finger, E., Seeley, W. W., Hatanpaa, K. J., Lomen-Hoerth, C., Kertesz, A., Bigio, E. H., Lippa, C., Woodruff, B. K., Knopman, D. S., White, C. L., ... Rademakers, R. (2011). Ataxin-2 repeat-length variation and neurodegeneration. Human molecular genetics, 20(16), 3207-3212. https://doi.org/10.1093/hmg/ddr227

@article{7db4ab6c13d9429a9e23668c7b8a69a1,

title = "Ataxin-2 repeat-length variation and neurodegeneration",

abstract = "Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR 5 5.57; P 5 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR 5 5.83; P 5 0.004; repeat length >30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31-33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.",

author = "Ross, {Owen A.} and Rutherford, {Nicola J.} and Matt Baker and Soto-Ortolaza, {Alexandra I.} and Carrasquillo, {Minerva M.} and Mariely DeJesus-Hernandez and Jennifer Adamson and Ma Li and Kathryn Volkening and Elizabeth Finger and Seeley, {William W.} and Hatanpaa, {Kimmo J.} and Catherine Lomen-Hoerth and Andrew Kertesz and Bigio, {Eileen H.} and Carol Lippa and Woodruff, {Bryan K.} and Knopman, {David S.} and White, {Charles L.} and {Van Gerpen}, {Jay A.} and Meschia, {James F.} and Mackenzie, {Ian R.} and Kevin Boylan and Boeve, {Bradley F.} and Miller, {Bruce L.} and Strong, {Michael J.} and Uitti, {Ryan J.} and Younkin, {Steven G.} and Graff-Radford, {Neill R.} and Petersen, {Ronald C.} and Wszolek, {Zbigniew K.} and Dickson, {Dennis W.} and Rosa Rademakers",

note = "Funding Information: This work was supported by the National Institutes of Health [grant numbers R01 NS065782 P50 AG16574 (Mayo ADRC RCP PI; to R.R., B.F.B., N.R.G.-R., D.W.D., S.G.Y.), U01 AG06576 (Mayo Alzheimer{\textquoteright}s Disease Patient Registry: RCP PI); R01 NS065782 (R.R.), R01 AG26251 (R.R.), R01 AG18023 (N.R.G.-R., S.G.Y.), AG1657303 (B.L.M., W.W.S.), AG25711 (D.W.D.), AG17216 (D.W.D.), AG03 949 (D.W.D.), AG13854 (E.H.B.), P30 AG19610 – 01 (Arizona Alzheimer{\textquoteright}s Disease Consortium: B.K.W.)] and the Peebler PSP Research Foundation (R.R.) and the ALS association (R.R.). Mayo Clinic Jacksonville is a Morris K. Udall Parkinson{\textquoteright}s Disease Research Center of Excellence supported by the NINDS [grant number P50 #NS072187]. Z.K.W. is also partially funded by the National Institutes of Health [grant numbers R01 NS057567 and 1RC2NS070276] and by Mayo Clinic Florida CR programs (MCF 90052018 and MCF 90052030). O.A.R., D.W.D., Z.K.W. and R.J.U. are supported by the family of Carl and Susan Bolch. K.J.H. and C.L.W. were supported by National Institutes of Health [grant number 5P30AG012300], the Winspear Family Center for Research on the Neuropathology of Alzheimer Disease and the McCune Foundation. I.R.M. was supported by the Canadian Institutes of Health Research Operating [#74580] and the Pacific Alzheimer{\textquoteright}s Disease Research Foundation. This project was also generously supported by the Robert and Clarice Smith and Abigail Van Buren Alzheimer{\textquoteright}s Disease Research Program (R.C.P., D.W.D., N.R.G.-R., S.G.Y.) and by the Palumbo Professorship in Alzheimer{\textquoteright}s Disease Research (S.G.Y.). ISGS samples were collected under funding from National Institute of Neurological Disorders and Stroke [grant number R01 NS42733 (J.F.M.)].",

year = "2011",

month = aug,

doi = "10.1093/hmg/ddr227",

language = "English (US)",

volume = "20",

pages = "3207--3212",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "16",

}

Ross, OA, Rutherford, NJ, Baker, M, Soto-Ortolaza, AI, Carrasquillo, MM, DeJesus-Hernandez, M, Adamson, J, Li, M, Volkening, K, Finger, E, Seeley, WW, Hatanpaa, KJ, Lomen-Hoerth, C, Kertesz, A, Bigio, EH, Lippa, C, Woodruff, BK, Knopman, DS, White, CL, Van Gerpen, JA, Meschia, JF, Mackenzie, IR, Boylan, K, Boeve, BF, Miller, BL, Strong, MJ, Uitti, RJ, Younkin, SG, Graff-Radford, NR, Petersen, RC, Wszolek, ZK, Dickson, DW & Rademakers, R 2011, 'Ataxin-2 repeat-length variation and neurodegeneration', Human molecular genetics, vol. 20, no. 16, pp. 3207-3212. https://doi.org/10.1093/hmg/ddr227

TY - JOUR

T1 - Ataxin-2 repeat-length variation and neurodegeneration

AU - Ross, Owen A.

AU - Rutherford, Nicola J.

AU - Baker, Matt

AU - Soto-Ortolaza, Alexandra I.

AU - Carrasquillo, Minerva M.

AU - DeJesus-Hernandez, Mariely

AU - Adamson, Jennifer

AU - Li, Ma

AU - Volkening, Kathryn

AU - Finger, Elizabeth

AU - Seeley, William W.

AU - Hatanpaa, Kimmo J.

AU - Lomen-Hoerth, Catherine

AU - Kertesz, Andrew

AU - Bigio, Eileen H.

AU - Lippa, Carol

AU - Woodruff, Bryan K.

AU - Knopman, David S.

AU - White, Charles L.

AU - Van Gerpen, Jay A.

AU - Meschia, James F.

AU - Mackenzie, Ian R.

AU - Boylan, Kevin

AU - Boeve, Bradley F.

AU - Miller, Bruce L.

AU - Strong, Michael J.

AU - Uitti, Ryan J.

AU - Younkin, Steven G.

AU - Graff-Radford, Neill R.

AU - Petersen, Ronald C.

AU - Wszolek, Zbigniew K.

AU - Dickson, Dennis W.

AU - Rademakers, Rosa

N1 - Funding Information: This work was supported by the National Institutes of Health [grant numbers R01 NS065782 P50 AG16574 (Mayo ADRC RCP PI; to R.R., B.F.B., N.R.G.-R., D.W.D., S.G.Y.), U01 AG06576 (Mayo Alzheimer’s Disease Patient Registry: RCP PI); R01 NS065782 (R.R.), R01 AG26251 (R.R.), R01 AG18023 (N.R.G.-R., S.G.Y.), AG1657303 (B.L.M., W.W.S.), AG25711 (D.W.D.), AG17216 (D.W.D.), AG03 949 (D.W.D.), AG13854 (E.H.B.), P30 AG19610 – 01 (Arizona Alzheimer’s Disease Consortium: B.K.W.)] and the Peebler PSP Research Foundation (R.R.) and the ALS association (R.R.). Mayo Clinic Jacksonville is a Morris K. Udall Parkinson’s Disease Research Center of Excellence supported by the NINDS [grant number P50 #NS072187]. Z.K.W. is also partially funded by the National Institutes of Health [grant numbers R01 NS057567 and 1RC2NS070276] and by Mayo Clinic Florida CR programs (MCF 90052018 and MCF 90052030). O.A.R., D.W.D., Z.K.W. and R.J.U. are supported by the family of Carl and Susan Bolch. K.J.H. and C.L.W. were supported by National Institutes of Health [grant number 5P30AG012300], the Winspear Family Center for Research on the Neuropathology of Alzheimer Disease and the McCune Foundation. I.R.M. was supported by the Canadian Institutes of Health Research Operating [#74580] and the Pacific Alzheimer’s Disease Research Foundation. This project was also generously supported by the Robert and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program (R.C.P., D.W.D., N.R.G.-R., S.G.Y.) and by the Palumbo Professorship in Alzheimer’s Disease Research (S.G.Y.). ISGS samples were collected under funding from National Institute of Neurological Disorders and Stroke [grant number R01 NS42733 (J.F.M.)].

PY - 2011/8

Y1 - 2011/8

N2 - Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR 5 5.57; P 5 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR 5 5.83; P 5 0.004; repeat length >30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31-33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.

AB - Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR 5 5.57; P 5 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR 5 5.83; P 5 0.004; repeat length >30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31-33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.

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UR - http://www.scopus.com/inward/citedby.url?scp=79960811611&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddr227

DO - 10.1093/hmg/ddr227

M3 - Article

C2 - 21610160

AN - SCOPUS:79960811611

SN - 0964-6906

VL - 20

SP - 3207

EP - 3212

JO - Human molecular genetics

JF - Human molecular genetics

IS - 16

ER -

Ataxin-2 repeat-length variation and neurodegeneration

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