Novel exon 1 progranulin gene variant in Alzheimer’s disease

Authors

  • F. Cortini,

    1. Department of Neurological Sciences, “Dino Ferrari” Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy
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    • *

      Contributed equally to this work.

  • C. Fenoglio,

    1. Department of Neurological Sciences, “Dino Ferrari” Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy
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    • *

      Contributed equally to this work.

  • I. Guidi,

    1. Department of Neurological Sciences, “Dino Ferrari” Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy
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  • E. Venturelli,

    1. Department of Neurological Sciences, “Dino Ferrari” Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy
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  • S. Pomati,

    1. Centre for Research and Treatment on Cognitive Dysfunctions, Chair of Neurology, University of Milan, “Luigi Sacco” Hospital, Milan, Italy
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  • A. Marcone,

    1. Division of Neurology, San Raffaele Turro Hospital, San Raffaele Scientific Institute, Milan, Italy
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  • D. Scalabrini,

    1. Department of Neurological Sciences, “Dino Ferrari” Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy
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  • C. Villa,

    1. Department of Neurological Sciences, “Dino Ferrari” Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy
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  • F. Clerici,

    1. Centre for Research and Treatment on Cognitive Dysfunctions, Chair of Neurology, University of Milan, “Luigi Sacco” Hospital, Milan, Italy
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  • E. Dalla Valle,

    1. Department of Neurological Sciences, “Dino Ferrari” Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy
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  • C. Mariani,

    1. Centre for Research and Treatment on Cognitive Dysfunctions, Chair of Neurology, University of Milan, “Luigi Sacco” Hospital, Milan, Italy
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  • S. Cappa,

    1. Division of Neurology, San Raffaele Turro Hospital, San Raffaele Scientific Institute, Milan, Italy
    2. Vita-Salute San Raffaele University, Milan, Italy
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  • N. Bresolin,

    1. Department of Neurological Sciences, “Dino Ferrari” Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy
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  • E. Scarpini,

    1. Department of Neurological Sciences, “Dino Ferrari” Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy
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  • D. Galimberti

    1. Department of Neurological Sciences, “Dino Ferrari” Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy
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Daniela Galimberti, Department of Neurological Sciences, “Dino Ferrari” Center, University of Milan, IRCCS Fondazione Ospedale Maggiore Policlinico, Milan, Italy (tel.: +39 2 55033858; fax: +39 2 50320430; e-mail: daniela.galimberti@unimi.it).

Abstract

Background and purpose:  Progranulin (PGRN) expression is increased in activated microglia in Alzheimer's disease (AD) brain, suggesting a potential role in this pathology.

Methods:  A mutation scanning of exons and flanking regions of PGRN was carried out in 120 patients with sporadic frontotemporal lobar degeneration and 145 with sporadic AD.

Results:  Amongst variants not yet deposited, a novel allelic variant was identified in Exon 1 (g100169A). It leads to an amino acidic change (p.Gly35Arg) and was observed in a patient with late onset AD. In silico analysis predicted that this mutation is possibly damaging. A second variant (g.100165T), resulting in a silent mutation (pAsp33Asp), was found in a patient with semantic dementia and in another with early onset AD. Both variants were absent in 226 controls. In addition, two rare non-pathogenic variants lying very close to PGRN splice-site regions (IVS2 + 7→G > A and IVS7 + 7→G > A) were observed. Transcriptional analysis in peripheral blood mononuclear cells from patients demonstrated they do not affect exon splicing.

Conclusions:  A novel putative PGRN mutation leading to an amino acidic substitution was identified in a patient with clinical AD.

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