Expression profiling in peripheral blood reveals signature for penetrance in DYT1 dystonia

M. Walter; M. Bonin; R. Saunders Pullman; E. M. Valente; M. Loi; M. Gambarin; D. Raymond; M. Tinazzi; C. Kamm; N. Glöckle; S. Poths; T. Gasser; S. B. Bressman; C. Klein; L. J. Ozelius; O. Riess; K. Grundmann

doi:10.1016/j.nbd.2009.12.019

Expression profiling in peripheral blood reveals signature for penetrance in DYT1 dystonia

M. Walter, M. Bonin, R. Saunders Pullman, E. M. Valente, M. Loi, M. Gambarin, D. Raymond, M. Tinazzi, C. Kamm, N. Glöckle, S. Poths, T. Gasser, S. B. Bressman, C. Klein, L. J. Ozelius, O. Riess, K. Grundmann^*

^*Corresponding author for this work

Institute of Neurogenetics

15 Citations (Scopus)

Abstract

DYT1 dystonia is an autosomal-dominantly inherited movement disorder, which is usually caused by a GAG deletion in the TOR1A gene. Due to the reduced penetrance of ̃ 30-40%, the determination of the mutation in a subject is of limited use with regard to actual manifestation of symptoms.In the present study, we used Affymetrix oligonucleotide microarrays to analyze global gene expression in blood samples of 15 manifesting and 15 non-manifesting mutation carriers in order to identify a susceptibility profile beyond the GAG deletion which is associated with the manifestation of symptoms in DYT1 dystonia.We identified a genetic signature which distinguished between asymptomatic mutation carriers and symptomatic DYT1 patients with 86.7% sensitivity and 100% specificity. This genetic signature could correctly predict the disease state in an independent test set with a sensitivity of 87.5% and a specificity of 85.7%.Conclusively, this genetic signature might provide a possibility to distinguish DYT1 patients from asymptomatic mutation carriers.

Original language	English
Journal	Neurobiology of Disease
Volume	38
Issue number	2
Pages (from-to)	192-200
Number of pages	9
ISSN	0969-9961
DOIs	https://doi.org/10.1016/j.nbd.2009.12.019
Publication status	Published - 01.05.2010

Funding

This work was supported by research grants from the Dystonia Medical Research Foundation (LO, SBB, RSP), the National Institute of Neurological Disorders and Stroke ( NS26636 , LJO & SBB; K23NS047256 , RSP; NS38142 LJO). CK is a recipient of a career development award from the Volkswagen Foundation (Lichtenberg Grant) and from the Hermann and Lilly Schilling Foundation (Schilling Grant). We thank Peter Bauer for diagnostic analysis of some DYT1 patients and for insightful comments. We further thank Dr. A. Renneberg for contributing patients to the study. We are grateful for patient's support. We thank all patients and family members who participated in this study. Appendix A Figure 1 Comparison between Microarray data and qPCR measurement. Each spot represents the Z -score of a single sample. Horizontal bars represent the median Z -score of the corresponding data points. Gene names and Affymetrix probeset IDs are given on top of each panel. Supplementary material Supplementary table Appendix A

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10.1016/j.nbd.2009.12.019

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Walter, M., Bonin, M., Pullman, R. S., Valente, E. M., Loi, M., Gambarin, M., Raymond, D., Tinazzi, M., Kamm, C., Glöckle, N., Poths, S., Gasser, T., Bressman, S. B., Klein, C., Ozelius, L. J., Riess, O., & Grundmann, K. (2010). Expression profiling in peripheral blood reveals signature for penetrance in DYT1 dystonia. Neurobiology of Disease, 38(2), 192-200. https://doi.org/10.1016/j.nbd.2009.12.019

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title = "Expression profiling in peripheral blood reveals signature for penetrance in DYT1 dystonia",

abstract = "DYT1 dystonia is an autosomal-dominantly inherited movement disorder, which is usually caused by a GAG deletion in the TOR1A gene. Due to the reduced penetrance of{\~ } 30-40\%, the determination of the mutation in a subject is of limited use with regard to actual manifestation of symptoms.In the present study, we used Affymetrix oligonucleotide microarrays to analyze global gene expression in blood samples of 15 manifesting and 15 non-manifesting mutation carriers in order to identify a susceptibility profile beyond the GAG deletion which is associated with the manifestation of symptoms in DYT1 dystonia.We identified a genetic signature which distinguished between asymptomatic mutation carriers and symptomatic DYT1 patients with 86.7\% sensitivity and 100\% specificity. This genetic signature could correctly predict the disease state in an independent test set with a sensitivity of 87.5\% and a specificity of 85.7\%.Conclusively, this genetic signature might provide a possibility to distinguish DYT1 patients from asymptomatic mutation carriers.",

author = "M. Walter and M. Bonin and Pullman, \{R. Saunders\} and Valente, \{E. M.\} and M. Loi and M. Gambarin and D. Raymond and M. Tinazzi and C. Kamm and N. Gl{\"o}ckle and S. Poths and T. Gasser and Bressman, \{S. B.\} and C. Klein and Ozelius, \{L. J.\} and O. Riess and K. Grundmann",

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Walter, M, Bonin, M, Pullman, RS, Valente, EM, Loi, M, Gambarin, M, Raymond, D, Tinazzi, M, Kamm, C, Glöckle, N, Poths, S, Gasser, T, Bressman, SB, Klein, C, Ozelius, LJ, Riess, O & Grundmann, K 2010, 'Expression profiling in peripheral blood reveals signature for penetrance in DYT1 dystonia', Neurobiology of Disease, vol. 38, no. 2, pp. 192-200. https://doi.org/10.1016/j.nbd.2009.12.019

TY - JOUR

T1 - Expression profiling in peripheral blood reveals signature for penetrance in DYT1 dystonia

AU - Walter, M.

AU - Bonin, M.

AU - Pullman, R. Saunders

AU - Valente, E. M.

AU - Loi, M.

AU - Gambarin, M.

AU - Raymond, D.

AU - Tinazzi, M.

AU - Kamm, C.

AU - Glöckle, N.

AU - Poths, S.

AU - Gasser, T.

AU - Bressman, S. B.

AU - Klein, C.

AU - Ozelius, L. J.

AU - Riess, O.

AU - Grundmann, K.

PY - 2010/5/1

Y1 - 2010/5/1

N2 - DYT1 dystonia is an autosomal-dominantly inherited movement disorder, which is usually caused by a GAG deletion in the TOR1A gene. Due to the reduced penetrance of ̃ 30-40%, the determination of the mutation in a subject is of limited use with regard to actual manifestation of symptoms.In the present study, we used Affymetrix oligonucleotide microarrays to analyze global gene expression in blood samples of 15 manifesting and 15 non-manifesting mutation carriers in order to identify a susceptibility profile beyond the GAG deletion which is associated with the manifestation of symptoms in DYT1 dystonia.We identified a genetic signature which distinguished between asymptomatic mutation carriers and symptomatic DYT1 patients with 86.7% sensitivity and 100% specificity. This genetic signature could correctly predict the disease state in an independent test set with a sensitivity of 87.5% and a specificity of 85.7%.Conclusively, this genetic signature might provide a possibility to distinguish DYT1 patients from asymptomatic mutation carriers.

AB - DYT1 dystonia is an autosomal-dominantly inherited movement disorder, which is usually caused by a GAG deletion in the TOR1A gene. Due to the reduced penetrance of ̃ 30-40%, the determination of the mutation in a subject is of limited use with regard to actual manifestation of symptoms.In the present study, we used Affymetrix oligonucleotide microarrays to analyze global gene expression in blood samples of 15 manifesting and 15 non-manifesting mutation carriers in order to identify a susceptibility profile beyond the GAG deletion which is associated with the manifestation of symptoms in DYT1 dystonia.We identified a genetic signature which distinguished between asymptomatic mutation carriers and symptomatic DYT1 patients with 86.7% sensitivity and 100% specificity. This genetic signature could correctly predict the disease state in an independent test set with a sensitivity of 87.5% and a specificity of 85.7%.Conclusively, this genetic signature might provide a possibility to distinguish DYT1 patients from asymptomatic mutation carriers.

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EP - 200

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ER -

Expression profiling in peripheral blood reveals signature for penetrance in DYT1 dystonia

Abstract

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