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Small CGG repeat expansion alleles of FMR1 gene are associated with parkinsonism

Authors

  • DZ Loesch,

    Corresponding author
    1. School of Psychological Science, La Trobe University, Melbourne/Bundoora, Victoria, Australia
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  • MS Khaniani,

    1. Chromosome and Chromatin Research Laboratory, The Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne/Parkville, Victoria, Australia
    2. Medical Genetics Division, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
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  • HR Slater,

    1. Department of Paediatrics, University of Melbourne/Parkville, Victoria, Australia
    2. Cytomolecular Diagnostic Research, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne/Parkville, Victoria, Australia
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  • JP Rubio,

    1. Florey Neurosciences Institute, University of Melbourne/Parkville, Victoria, Australia
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  • QM Bui,

    1. Centre for Molecular, Environmental, Genetic and Analytic, Epidemiology, University of Melbourne/Parkville, Victoria, Australia
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  • K Kotschet,

    1. St Vincent's Hospital, Melbourne/Fitzroy, Victoria, Australia
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  • W D’Souza,

    1. St Vincent's Hospital, Melbourne/Fitzroy, Victoria, Australia
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  • A Venn,

    1. Menzies Research Institute, University of Tasmania, Hobart, Australia
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  • P Kalitsis,

    1. Chromosome and Chromatin Research Laboratory, The Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne/Parkville, Victoria, Australia
    2. Department of Paediatrics, University of Melbourne/Parkville, Victoria, Australia
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  • AKH Choo,

    1. Chromosome and Chromatin Research Laboratory, The Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne/Parkville, Victoria, Australia
    2. Department of Paediatrics, University of Melbourne/Parkville, Victoria, Australia
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  • T Burgess,

    1. Cytomolecular Diagnostic Research, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne/Parkville, Victoria, Australia
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  • L Johnson,

    1. Florey Neurosciences Institute, University of Melbourne/Parkville, Victoria, Australia
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  • A Evans,

    1. Department of Neurology, Royal Melbourne Hospital, Parkville, Victoria, Australia
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  • M Horne

    1. Florey Neurosciences Institute, University of Melbourne/Parkville, Victoria, Australia
    2. Centre for Molecular, Environmental, Genetic and Analytic, Epidemiology, University of Melbourne/Parkville, Victoria, Australia
    3. Centre for Neuroscience, University of Melbourne/Parkville, Victoria, Australia
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Dr Danuta Z Loesch, School of Psychological Science, La Trobe University, Victoria 3086, Australia.
Tel: 61 3 94791382;
fax: 61 3 94791956;
e-mail: d.loesch@latrobe.edu.au

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) affects older males carrying premutation, that is, expansions of the CGG repeat (in the 55–200 range), in the FMR1 gene. The neurological changes are linked to the excessive FMR1 messenger RNA (mRNA), becoming toxic through a ‘gain-of-function’. Because elevated levels of this mRNA are also found in carriers of the smaller expansion (grey zone) alleles, ranging from 40 to 54 CGGs, we tested for a possible role of these alleles in the origin of movement disorders associated with tremor.

We screened 228 Australian males affected with idiopathic Parkinson's disease and other causes of parkinsonism recruited from Victoria and Tasmania for premutation and grey zone alleles. The frequencies of either of these alleles were compared with the frequencies in a population-based sample of 578 Guthrie spots from consecutive Tasmanian male newborns (controls). There was a significant excess of premutation carriers (Fisher's exact test p = 0.006). There was also a more than twofold increase in grey zone carriers in the combined sample of the Victorian and Tasmanian cases, with odds ratio (OR ) = 2.36, and 95% confidence intervals (CI): 1.20–4.63, as well as in Tasmanian cases only (OR = 2.33, 95% CI: 1.06–5.13), compared with controls. The results suggest that the FMR1 grey zone alleles, as well as premutation alleles, might contribute to the aetiology of disorders associated with parkinsonism.

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