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

Neurobiology of Disease (May 2010)

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

Affiliations

M. Walter: Department of Medical Genetics, Institute of Human Genetics, University of Tuebingen, Calwer Str. 7, D-72076 Tuebingen, Germany; Microarray Facility Tuebingen, Institute of Human Genetics, University of Tuebingen, Calwer Str.7, 72076 Tuebingen Germany
M. Bonin: Department of Medical Genetics, Institute of Human Genetics, University of Tuebingen, Calwer Str. 7, D-72076 Tuebingen, Germany; Microarray Facility Tuebingen, Institute of Human Genetics, University of Tuebingen, Calwer Str.7, 72076 Tuebingen Germany
R. Saunders Pullman: Department of Neurology, Beth Israel Medical Center, Union Square East New York, NY 10003-3314, USA; Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA
E.M. Valente: IRCCS Casa Sollievo della Sofferenza, CSS-Mendel Institute, viale Regina Margherita 261, 00198 Rome, Italy; Department of Medical and Surgical Pediatric Sciences, University of Messina, Policlinico, Via Consolare Valeria, Pad. NI, Messina, Italy
M. Loi: Department of Neuropsychiatry, G. Brotzu Hospital, Via Peretti, Cagliari, Sardegna 09139 Italy
M. Gambarin: Department of Neurological and Visual Sciences, University of Verona, Policlinico “G.B. Rossi”, P.le L.A. Scuro 10, 37134 Verona, Italy
D. Raymond: Department of Neurology, Beth Israel Medical Center, Union Square East New York, NY 10003-3314, USA
M. Tinazzi: Department of Neurological and Visual Sciences, University of Verona, Policlinico “G.B. Rossi”, P.le L.A. Scuro 10, 37134 Verona, Italy
C. Kamm: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases Otfried-Müller-Straße 27, 72076 Tübingen, Germany
N. Glöckle: Department of Medical Genetics, Institute of Human Genetics, University of Tuebingen, Calwer Str. 7, D-72076 Tuebingen, Germany
S. Poths: Department of Medical Genetics, Institute of Human Genetics, University of Tuebingen, Calwer Str. 7, D-72076 Tuebingen, Germany; Microarray Facility Tuebingen, Institute of Human Genetics, University of Tuebingen, Calwer Str.7, 72076 Tuebingen Germany
T. Gasser: Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases Otfried-Müller-Straße 27, 72076 Tübingen, Germany
S.B. Bressman: Department of Neurology, Beth Israel Medical Center, Union Square East New York, NY 10003-3314, USA
C. Klein: Section of Clinical and Molecular Neurogenetics at the Department of Neurology, University of Luebeck, Maria-Goeppert-Str. 1, 23562 Luebeck, Germany
L.J. Ozelius: Departments of Genetics and Genomic Sciences and Neurology, Mount Sinai School of Medicine, One Gustave L Levy Place, Box 1498, New York, NY 10029, USA
O. Riess: Department of Medical Genetics, Institute of Human Genetics, University of Tuebingen, Calwer Str. 7, D-72076 Tuebingen, Germany
K. Grundmann: Department of Medical Genetics, Institute of Human Genetics, University of Tuebingen, Calwer Str. 7, D-72076 Tuebingen, Germany; Corresponding author. Fax: +49 7071 5171.

Journal volume & issue: Vol. 38, no. 2
pp. 192 – 200

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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