Progranulin locus deletion in frontotemporal dementia

Authors

  • I. Gijselinck,

    1. Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), University of Antwerp, Antwerpen, Belgium
    2. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
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  • J. van der Zee,

    1. Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), University of Antwerp, Antwerpen, Belgium
    2. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
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  • S. Engelborghs,

    1. Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
    2. Memory Clinic, Division of Neurology, Middelheim General Hospital, Antwerpen, Belgium
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  • D. Goossens,

    1. Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), University of Antwerp, Antwerpen, Belgium
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  • K. Peeters,

    1. Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), University of Antwerp, Antwerpen, Belgium
    2. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
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  • M. Mattheijssens,

    1. Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), University of Antwerp, Antwerpen, Belgium
    2. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
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  • E. Corsmit,

    1. Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), University of Antwerp, Antwerpen, Belgium
    2. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
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  • J. Del-Favero,

    1. Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), University of Antwerp, Antwerpen, Belgium
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  • P.P. De Deyn,

    1. Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
    2. Memory Clinic, Division of Neurology, Middelheim General Hospital, Antwerpen, Belgium
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  • C. Van Broeckhoven,

    1. Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), University of Antwerp, Antwerpen, Belgium
    2. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
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  • M. Cruts

    Corresponding author
    1. Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Institute for Biotechnology (VIB), University of Antwerp, Antwerpen, Belgium
    2. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
    • Neurodegenerative Brain Diseases Group, VIB-Department of Molecular Genetics, University of Antwerp-CDE, Universiteitsplein 1, BE-2610 Antwerpen, Belgium
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  • Communicated by Haig H. Kazazian, Jr.

Abstract

Ubiquitin-positive, tau-negative, frontotemporal dementia (FTD) is caused by null mutations in progranulin (PGRN; HUGO gene symbol GRN), suggesting a haploinsufficiency mechanism. Since whole gene deletions also lead to the loss of a functional allele, we performed systematic quantitative analyses of PGRN in a series of 103 Belgian FTD patients. We identified in one patient (1%) a genomic deletion that was absent in 267 control individuals. The deleted segment was between 54 and 69 kb in length and comprised PGRN and two centromeric neighboring genes RPIP8 (HUGO gene symbol RUNDC3A) and SLC25A39. The patient presented clinically with typical FTD without additional symptoms, consistent with haploinsufficiency of PGRN being the only gene contributing to the disease phenotype. This study demonstrates that reduced PGRN in absence of mutant protein is sufficient to cause neurodegeneration and that previously reported PGRN mutation frequencies are underestimated. Hum Mutat 29(1), 53–58, 2008. © 2007 Wiley-Liss, Inc.

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