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HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin

Authors

  • Odity Mukherjee PhD,

    1. Washington University 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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  • Pau Pastor MD, PhD,

    1. Washington University 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
    3. School of Medicine University of Navarre, Pamplona and Division of Neurosciences, Center for Applied Medical Research (CIMA), Clínica Universitaria
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  • Nigel J. Cairns PhD,

    1. Washington University Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
    3. Department of Neurology, Washington University School of Medicine, St. Louis, MO
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  • Sumi Chakraverty MS,

    1. Washington University 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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  • John S. K. Kauwe MS,

    1. Washington University 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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  • Shantia Shears BS,

    1. Washington University 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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  • Maria I. Behrens MD, PhD,

    1. Washington University Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Departamento de Neurología, Facultad de Medicina, Universidad de Chile Clínica Alemana, Santiago, Chile
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  • John Budde BS,

    1. Washington University 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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  • Anthony L. Hinrichs PhD,

    1. Washington University 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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  • Joanne Norton MSN, RN, CS,

    1. Washington University 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 BS, RN,

    1. Washington University 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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  • Lisa Taylor-Reinwald BA,

    1. Washington University 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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  • Michael Gitcho PhD,

    1. Washington University 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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  • P.-H. Tu MD, PhD,

    1. Washington University Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
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  • Lea Tenenholz Grinberg MD,

    1. Washington University Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
    3. Department of Pathology, University of Sao Paulo Medical School, Sao Paulo, Brazil
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  • Rajka M. Liscic MD, PhD,

    1. Washington University Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
    3. Institute for Medical Research and Occupational Health, Zagreb, Croatia
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  • Javier Armendariz MS,

    1. School of Medicine University of Navarre, Pamplona and Division of Neurosciences, Center for Applied Medical Research (CIMA), Clínica Universitaria
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  • John C. Morris MD,

    1. Washington University Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO
    2. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
    3. Department of Neurology, Washington University School of Medicine, St. Louis, MO
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  • Alison M. Goate PhD

    Corresponding author
    1. Washington University 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
    3. Department of Neurology, Washington University School of Medicine, St. Louis, MO
    4. Department of Genetics, Washington University School of Medicine, St. Louis, MO
    • Department of Psychiatry, Washington University School of Medicine, Campus Box 8134, 660 South Euclid Avenue, St. Louis, MO 63110
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Abstract

Objective

Familial autosomal dominant frontotemporal dementia with ubiquitin-positive, tau-negative inclusions in the brain linked to 17q21-22 recently has been reported to carry null mutations in the progranulin gene (PGRN). Hereditary dysphasic disinhibition dementia (HDDD) is a frontotemporal dementia with prominent changes in behavior and language deficits. A previous study found significant linkage to chromosome 17 in a HDDD family (HDDD2), but no mutation in the MAPT gene. Longitudinal follow-up has enabled us to identify new cases and to further characterize the dementia in this family. The goals of this study were to develop research criteria to classify the different clinical expressions of dementia observed in this large kindred, to identify the causal mutation in affected individuals and correlate this with phenotypic characteristics in this pedigree, and to assess the neuropathological characteristics using immunohistochemical techniques.

Methods

In this study we describe a detailed clinical, pathological and mutation analysis of the HDDD2 kindred.

Results

Neuropathologically, HDDD2 represents a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U). We developed research classification criteria and identified three distinct diagnostic thresholds, which helped localize the disease locus. The chromosomal region with the strongest evidence of linkage lies within the minimum critical region for FTLD-U. Sequencing of each exon of the PGRN gene led to the identification of a novel missense mutation, Ala-9 Asp, within the signal peptide.

Interpretation

HDDD2 is an FTLD-U caused by a missense mutation in the PGRN gene that cosegregates with the disease and with the disease haplotype in at-risk individuals. This mutation is the first reported pathogenic missense mutation in the signal peptide of the PGRN gene causing FTLD-U. In light of the previous reports of null mutations and its position in the gene, two possible pathological mechanisms are proposed: (1) the protein may accumulate within the endoplasmic reticulum due to inefficient secretion; and (2) mutant RNA may have a lower expression because of degradation via nonsense-mediated decay. Ann Neurol 2006;60:314–322

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