TDP-43 A315T mutation in familial motor neuron disease

Authors

  • Michael A. Gitcho PhD,

    1. Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Department of Neurology, Washington University School of Medicine, St. Louis, MO
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    • M.A.G. and R.H.B. contributed equally to this work.

  • Robert H. Baloh MD, PhD,

    1. Department of Neurology, Washington University School of Medicine, St. Louis, MO
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    • M.A.G. and R.H.B. contributed equally to this work.

  • Sumi Chakraverty MS,

    1. Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO
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  • Kevin Mayo BS,

    1. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO
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  • Joanne B. Norton RN,

    1. Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO
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  • Denise Levitch RN,

    1. Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO
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  • Kimmo J. Hatanpaa MD, PhD,

    1. Neuropathology Laboratory, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX
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  • Charles L. White III MD,

    1. Neuropathology Laboratory, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX
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  • Eileen H. Bigio MD,

    1. Department of Pathology, Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL
    2. Department of Cognitive Neurology, Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL
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  • Richard Caselli MD,

    1. Department of Neurology, Mayo Clinic, Scottsdale, AZ
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  • Matt Baker BSc,

    1. Department of Neuroscience, Mayo Clinic, Jacksonville, FL
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  • Muhammad T. Al-Lozi MBBS,

    1. Department of Neurology, Washington University School of Medicine, St. Louis, MO
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  • John C. Morris MD,

    1. Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Department of Neurology, Washington University School of Medicine, St. Louis, MO
    3. Departments of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
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  • Alan Pestronk MD,

    1. Department of Neurology, Washington University School of Medicine, St. Louis, MO
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  • Rosa Rademakers PhD,

    1. Department of Neuroscience, Mayo Clinic, Jacksonville, FL
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  • Alison M. Goate DPhil,

    1. Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Department of Neurology, Washington University School of Medicine, St. Louis, MO
    3. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO
    4. Department of Genetics, Washington University School of Medicine, St. Louis, MO
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  • Nigel J. Cairns PhD, FRCPath

    Corresponding author
    1. Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Department of Neurology, Washington University School of Medicine, St. Louis, MO
    3. Departments of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
    • Department of Pathology and Immunology and Alzheimer's Disease Center, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, Saint Louis, MO 63110
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Abstract

To identify novel causes of familial neurodegenerative diseases, we extended our previous studies of TAR DNA-binding protein 43 (TDP-43) proteinopathies to investigate TDP-43 as a candidate gene in familial cases of motor neuron disease. Sequencing of the TDP-43 gene led to the identification of a novel missense mutation, Ala-315-Thr, which segregates with all affected members of an autosomal dominant motor neuron disease family. The mutation was not found in 1,505 healthy control subjects. The discovery of a missense mutation in TDP-43 in a family with dominantly inherited motor neuron disease provides evidence of a direct link between altered TDP-43 function and neurodegeneration. Ann Neurol 2008

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