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Rare sequence variants in ANO3 and GNAL in a primary torsion dystonia series and controls

Authors

  • Michael Zech MD,

    1. Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
    2. Institut für Humangenetik, Munich, Germany
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  • Nadine Gross MD,

    1. Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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  • Angela Jochim MD,

    1. Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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  • Florian Castrop MD,

    1. Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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  • Maria Kaffe MD, PhD,

    1. Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
    2. Institut für Humangenetik, Munich, Germany
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  • Christian Dresel MD,

    1. Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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  • Peter Lichtner PhD,

    1. Institut für Humangenetik, Munich, Germany
    2. Institut für Humangenetik, Technische Universität München, Munich, Germany
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  • Annette Peters PhD,

    1. Institute of Epidemiology II, Munich, Germany
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  • Christian Gieger PhD,

    1. Institute of Genetic Epidemiology, Munich, Germany
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  • Thomas Meitinger MD,

    1. Institut für Humangenetik, Munich, Germany
    2. Institut für Humangenetik, Technische Universität München, Munich, Germany
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  • Bernhard Haslinger MD,

    1. Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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  • Juliane Winkelmann MD

    Corresponding author
    1. Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
    2. Institut für Humangenetik, Munich, Germany
    3. Institut für Humangenetik, Technische Universität München, Munich, Germany
    4. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, California, USA
    5. Munich Cluster for Systems Neurology, SyNergy, Munich, Germany
    • Correspondence to: Dr. Juliane Winkelmann, Neurologische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675 Munich, Germany; winkelmann@lrz.tum.de

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  • Funding agencies: This study as well as the recruitment of the case sample was funded by in-house institutional funding from Technische Universität München and Helmholtz Zentrum München, Munich, Germany. Recruitment of the control cohort was supported by institutional funding from Helmholtz Zentrum München, Munich, Germany, and government funding from the German Bundesministerium für Bildung und Forschung (BMBF, 03.2007-02.2011 FKZ 01ET0713).

  • Relevant conflicts of interest/financial disclosures: Nothing to report.

  • Full financial disclosures and author roles may be found in the online version of this article.

ABSTRACT

Background

Rare autosomal-dominant mutations in ANO3 and GNAL have been recently shown to represent novel genetic factors underlying primary torsion dystonia (PTD) with predominantly craniocervical involvement.

Methods

We used high-resolution melting to screen all exons of ANO3 and GNAL for rare sequence variants in a population of 342 German individuals with mainly sporadic PTD and 376 general population controls.

Results

We identified 2 novel missense variants in ANO3 (p.Ile833Val and p.Gly973Arg) and 1 novel missense variant in GNAL (p.Val146Met) in three different nonfamilial cases. Variant carriers presented with adult-onset dystonia involving the neck and/or face. In controls, 3 rare ANO3 missense variants (p.Tyr235Cys, p.Asn256Ser, and p.Pro893Leu) but no rare nonsynonymous GNAL variants were present.

Conclusions

GNAL variants seem to be a rare cause of PTD in our mainly sporadic German sample. Low frequency missense variants in ANO3 occur in both cases and controls, warranting further assessment of this gene in PTD pathogenesis. © 2013 International Parkinson and Movement Disorder Society

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