Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia

Authors

  • Odity Mukherjee,

    1. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
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  • Jun Wang,

    1. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
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  • Michael Gitcho,

    1. Department of Neurology, Washington University School of Medicine, St. Louis, Missouri
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  • Sumi Chakraverty,

    1. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
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  • Lisa Taylor-Reinwald,

    1. Department of Immunology & Pathology, Washington University School of Medicine, St. Louis, Missouri
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  • Shantia Shears,

    1. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
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  • John S.K. Kauwe,

    1. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
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  • Joanne Norton,

    1. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
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  • Denise Levitch,

    1. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
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  • Eileen H. Bigio,

    1. Division of Neuropathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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  • Kimmo J. Hatanpaa,

    1. Neuropathology Laboratory, Department of Pathology, University of Texas Southwestern (UTSW) Medical School, Dallas, Texas
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  • Charles L. White,

    1. Neuropathology Laboratory, Department of Pathology, University of Texas Southwestern (UTSW) Medical School, Dallas, Texas
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  • John C. Morris,

    1. Department of Immunology & Pathology, Washington University School of Medicine, St. Louis, Missouri
    2. Department of Neurology, Washington University School of Medicine, St. Louis, Missouri
    3. Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri
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  • Nigel J. Cairns,

    1. Department of Immunology & Pathology, Washington University School of Medicine, St. Louis, Missouri
    2. Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, Missouri
    3. Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri
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  • Alison Goate

    Corresponding author
    1. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
    2. Department of Neurology, Washington University School of Medicine, St. Louis, Missouri
    3. Department of Genetics, Washington University School of Medicine, St. Louis, Missouri
    4. Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, Missouri
    5. Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri
    • Department of Psychiatry, Washington University School of Medicine, Campus Box 8134, 660 South Euclid Avenue, St. Louis, MO 63110

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  • Communicated by Christine Van Broeckhoven

Abstract

Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimer's Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD-U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene (GRN; also PGRN). We discovered two pathogenic mutations in four families: 1) a single-base substitution within the 3′ splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6–2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency. Hum Mutat 29(4), 512–521, 2008. © 2008 Wiley-Liss, Inc.

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