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Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration–motor neuron disease

Authors

  • Agnes A. Luty BSc,

    1. Neuroscience Research Australia, Sydney, New South Wales, Australia
    2. School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
    3. Garvan Institute of Medical Research, Sydney, New South Wales, Australia
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    • These authors contributed equally to this work.

  • John B.J. Kwok PhD,

    1. Neuroscience Research Australia, Sydney, New South Wales, Australia
    2. School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
    3. Garvan Institute of Medical Research, Sydney, New South Wales, Australia
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    • These authors contributed equally to this work.

  • Carol Dobson-Stone PhD,

    1. Neuroscience Research Australia, Sydney, New South Wales, Australia
    2. School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
    3. Garvan Institute of Medical Research, Sydney, New South Wales, Australia
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    • These authors contributed equally to this work.

  • Clement T. Loy MD,

    1. Neuroscience Research Australia, Sydney, New South Wales, Australia
    2. School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
    3. Garvan Institute of Medical Research, Sydney, New South Wales, Australia
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  • Kirsten G. Coupland BSc,

    1. Neuroscience Research Australia, Sydney, New South Wales, Australia
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  • Helena Karlström PhD,

    1. Karolinska Institute, Stockholm, Sweden
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  • Tomasz Sobow MD,

    1. Department of Medical Psychology, Medical University of Lodz, Lodz, Poland
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  • Joanna Tchorzewska MD,

    1. Department of Medical Psychology, Medical University of Lodz, Lodz, Poland
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  • Aleksandra Maruszak BSc,

    1. Department of Neurodegenerative Disorders, Polish Academy of Sciences, Warsaw, Poland
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  • Maria Barcikowska MD,

    1. Department of Neurodegenerative Disorders, Polish Academy of Sciences, Warsaw, Poland
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  • Peter K. Panegyres MD,

    1. Neurosciences Unit, Department of Health, Perth, Western Australia, Australia
    2. Neurodegenerative Disorders Research, Subiaco, Western Australia, Australia
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  • Cezary Zekanowski PhD,

    1. Department of Neurodegenerative Disorders, Polish Academy of Sciences, Warsaw, Poland
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  • William S. Brooks MD,

    1. Neuroscience Research Australia, Sydney, New South Wales, Australia
    2. School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
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  • Kelly L. Williams BSc,

    1. Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, New South Wales, Australia
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  • Ian P. Blair PhD,

    1. Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, New South Wales, Australia
    2. Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia
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  • Karen A. Mather PhD,

    1. Brain and Ageing Research Program, School of Psychiatry, University of New South Wales, New South Wales, Australia
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  • Perminder S. Sachdev MD,

    1. Brain and Ageing Research Program, School of Psychiatry, University of New South Wales, New South Wales, Australia
    2. Neuropsychiatric Institute, The Prince of Wales Hospital, Sydney, New South Wales, Australia
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  • Glenda M. Halliday PhD,

    1. Neuroscience Research Australia, Sydney, New South Wales, Australia
    2. School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
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  • Peter R. Schofield PhD, DSc

    Corresponding author
    1. Neuroscience Research Australia, Sydney, New South Wales, Australia
    2. School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
    3. Garvan Institute of Medical Research, Sydney, New South Wales, Australia
    • Neuroscience Research Australia, Barker St, Randwick, Sydney, NSW 2031, Australia
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Abstract

Objective:

Frontotemporal lobar degeneration (FTLD) is the most common cause of early-onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) comprise trans-activating response element (TAR) DNA binding protein (TDP-43) and/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD-MND pedigree with no mutations in known dementia genes.

Methods:

A mutation screen of candidate genes, luciferase assays, and quantitative polymerase chain reaction (PCR) was performed to identify the biological role of the putative mutation. Neuropathological characterization of affected individuals and western blot studies of cell lines were performed to identify the pathological mechanism of the mutation.

Results:

We identified a nonpolymorphic mutation (c.672*51G>T) in the 3′-untranslated region (UTR) of the Sigma nonopioid intracellular receptor 1 (SIGMAR1) gene in affected individuals from the FTLD-MND pedigree. The c.672*51G>T mutation increased gene expression by 1.4-fold, corresponding with a significant 1.5-fold to 2-fold change in the SIGMAR1 transcript or Sigma-1 protein in lymphocyte or brain tissue. Brains of SIGMAR1 mutation carriers displayed a unique pathology with cytoplasmic inclusions immunopositive for either TDP-43 or FUS but not Sigma-1. Overexpression of SIGMAR1 shunted TDP-43 and FUS from the nucleus to the cytoplasm by 2.3-fold and 5.2-fold, respectively. Treatment of cells with Sigma-1 ligands significantly altered translocation of TDP-43 by up to 2-fold.

Interpretation:

SIGMAR1 is a causative gene for familial FTLD-MND with a unique neuropathology that differs from other FTLD and MND cases. Our findings also suggest Sigma-1 drugs as potential treatments for the TDP-43/FUS proteinopathies. Ann Neurol 2010;68:639–649

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