Advertisement
  • Open Access

A Pan-European Study of the C9orf72 Repeat Associated with FTLD: Geographic Prevalence, Genomic Instability, and Intermediate Repeats

Authors

  • Julie van der Zee,

    1. Department of Molecular Genetics, VIB, Antwerp, Belgium
    2. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    Search for more papers by this author
    • Authors Julie van der Zee and Ilse Gijselinck are the joint first authors.

  • Ilse Gijselinck,

    1. Department of Molecular Genetics, VIB, Antwerp, Belgium
    2. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    Search for more papers by this author
    • Authors Julie van der Zee and Ilse Gijselinck are the joint first authors.

  • Lubina Dillen,

    1. Department of Molecular Genetics, VIB, Antwerp, Belgium
    2. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    Search for more papers by this author
  • Tim Van Langenhove,

    1. Department of Molecular Genetics, VIB, Antwerp, Belgium
    2. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    Search for more papers by this author
  • Jessie Theuns,

    1. Department of Molecular Genetics, VIB, Antwerp, Belgium
    2. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    Search for more papers by this author
  • Sebastiaan Engelborghs,

    1. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    2. Department of Neurology and Memory Clinic, Hospital Network Antwerp, Middelheim and Hoge Beuken, Antwerp, Belgium
    Search for more papers by this author
  • Stéphanie Philtjens,

    1. Department of Molecular Genetics, VIB, Antwerp, Belgium
    2. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    Search for more papers by this author
  • Mathieu Vandenbulcke,

    1. Brain and Emotion Laboratory Leuven, Department of Psychiatry, University of Leuven and University Hospitals Leuven Gasthuisberg, Leuven, Belgium
    Search for more papers by this author
  • Kristel Sleegers,

    1. Department of Molecular Genetics, VIB, Antwerp, Belgium
    2. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    Search for more papers by this author
  • Anne Sieben,

    1. Department of Molecular Genetics, VIB, Antwerp, Belgium
    2. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    3. Department of Neurology, University Hospital Ghent and University of Ghent, Gent, Belgium
    Search for more papers by this author
  • Veerle Bäumer,

    1. Department of Molecular Genetics, VIB, Antwerp, Belgium
    2. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    Search for more papers by this author
  • Githa Maes,

    1. Department of Molecular Genetics, VIB, Antwerp, Belgium
    2. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    Search for more papers by this author
  • Ellen Corsmit,

    1. Department of Molecular Genetics, VIB, Antwerp, Belgium
    2. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    Search for more papers by this author
  • Barbara Borroni,

    1. Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy
    Search for more papers by this author
  • Alessandro Padovani,

    1. Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy
    Search for more papers by this author
  • Silvana Archetti,

    1. Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy
    Search for more papers by this author
  • Robert Perneczky,

    1. Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany
    Search for more papers by this author
  • Janine Diehl-Schmid,

    1. Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany
    Search for more papers by this author
  • Alexandre de Mendonça,

    1. Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
    Search for more papers by this author
  • Gabriel Miltenberger-Miltenyi,

    1. Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
    Search for more papers by this author
  • Sónia Pereira,

    1. Institute of Molecular Medicine, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
    Search for more papers by this author
  • José Pimentel,

    1. Faculty of Medicine, University of Lisbon, Lisbon, Portugal
    Search for more papers by this author
  • Benedetta Nacmias,

    1. Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy
    Search for more papers by this author
  • Silvia Bagnoli,

    1. Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy
    Search for more papers by this author
  • Sandro Sorbi,

    1. Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy
    Search for more papers by this author
  • Caroline Graff,

    1. Department of Neurobiology, Care Sciences and Society, KI-Alzheimer Disease Research Center, Karolinska Institutet, Stockholm, Sweden
    2. Department of Geriatric Medicine, Genetics unit, Karolinska University Hospital, Stockholm, Sweden
    Search for more papers by this author
  • Huei-Hsin Chiang,

    1. Department of Neurobiology, Care Sciences and Society, KI-Alzheimer Disease Research Center, Karolinska Institutet, Stockholm, Sweden
    Search for more papers by this author
  • Marie Westerlund,

    1. Department of Neurobiology, Care Sciences and Society, KI-Alzheimer Disease Research Center, Karolinska Institutet, Stockholm, Sweden
    Search for more papers by this author
  • Raquel Sanchez-Valle,

    1. Alzheimer's disease and Other cognitive disorders unit, Department of Neurology, Hospital Clinic, Barcelona, Spain
    Search for more papers by this author
  • Albert Llado,

    1. Alzheimer's disease and Other cognitive disorders unit, Department of Neurology, Hospital Clinic, Barcelona, Spain
    Search for more papers by this author
  • Ellen Gelpi,

    1. Biobanc, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
    Search for more papers by this author
  • Isabel Santana,

    1. Neurology Department, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal
    2. Faculty of Medicine, University of Coimbra, Coimbra, Portugal
    Search for more papers by this author
  • Maria Rosário Almeida,

    1. Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
    Search for more papers by this author
  • Beatriz Santiago,

    1. Neurology Department, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal
    Search for more papers by this author
  • Giovanni Frisoni,

    1. Laboratory of Epidemiology Neuroimaging & Telemedicine & National Centre for Alzheimer's and Mental Diseases, IRCCS Centro San Giovanni di Dio, FBF, Brescia, Italy
    Search for more papers by this author
  • Orazio Zanetti,

    1. Laboratory of Epidemiology Neuroimaging & Telemedicine & National Centre for Alzheimer's and Mental Diseases, IRCCS Centro San Giovanni di Dio, FBF, Brescia, Italy
    Search for more papers by this author
  • Cristian Bonvicini,

    1. Laboratory of Epidemiology Neuroimaging & Telemedicine & National Centre for Alzheimer's and Mental Diseases, IRCCS Centro San Giovanni di Dio, FBF, Brescia, Italy
    Search for more papers by this author
  • Matthis Synofzik,

    1. Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and Centre of Neurology, Tuebingen, Germany
    2. German Research Center for Neurodegenerative Diseases (DZNE), University of Tuebingen, Tuebingen, Germany
    Search for more papers by this author
  • Walter Maetzler,

    1. Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and Centre of Neurology, Tuebingen, Germany
    2. German Research Center for Neurodegenerative Diseases (DZNE), University of Tuebingen, Tuebingen, Germany
    Search for more papers by this author
  • Jennifer Müller vom Hagen,

    1. Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and Centre of Neurology, Tuebingen, Germany
    2. German Research Center for Neurodegenerative Diseases (DZNE), University of Tuebingen, Tuebingen, Germany
    Search for more papers by this author
  • Ludger Schöls,

    1. Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and Centre of Neurology, Tuebingen, Germany
    2. German Research Center for Neurodegenerative Diseases (DZNE), University of Tuebingen, Tuebingen, Germany
    Search for more papers by this author
  • Michael T. Heneka,

    1. Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Bonn, Germany
    2. German Center for Neurodegenerative Diseases (DZNE), University of Bonn, Bonn, Germany
    Search for more papers by this author
  • Frank Jessen,

    1. Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Bonn, Germany
    2. German Center for Neurodegenerative Diseases (DZNE), University of Bonn, Bonn, Germany
    3. Department of Psychiatry, University of Bonn, Bonn, Germany
    Search for more papers by this author
  • Radoslav Matej,

    1. Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague, Czech Republic
    Search for more papers by this author
  • Eva Parobkova,

    1. Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague, Czech Republic
    Search for more papers by this author
  • Gabor G. Kovacs,

    1. Institute of Neurology, Medical University Vienna, Vienna, Austria
    Search for more papers by this author
  • Thomas Ströbel,

    1. Institute of Neurology, Medical University Vienna, Vienna, Austria
    Search for more papers by this author
  • Stayko Sarafov,

    1. Department of Neurology, Medical University Sofia, Sofia, Bulgaria
    Search for more papers by this author
  • Ivailo Tournev,

    1. Department of Neurology, Medical University Sofia, Sofia, Bulgaria
    2. Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria
    Search for more papers by this author
  • Albena Jordanova,

    1. Department of Molecular Genetics, VIB, Antwerp, Belgium
    2. Department of Biochemistry, Molecular Medicine Center, Medical University, Sofia, Bulgaria
    Search for more papers by this author
  • Adrian Danek,

    1. Neurologische Klinik, Ludwig Maximilians Universität, Munich, Germany
    Search for more papers by this author
  • Thomas Arzberger,

    1. Zentrum für Neuropathologie und Prionforschung, Ludwig-Maximilians-Universität Munich, Munich, Germany
    Search for more papers by this author
  • Gian Maria Fabrizi,

    1. Section of Neuropathology, Department of Neurological, Neuropsychological, Morphological and Movement Sciences, University of Verona, Verona, Italy
    Search for more papers by this author
  • Silvia Testi,

    1. Section of Neuropathology, Department of Neurological, Neuropsychological, Morphological and Movement Sciences, University of Verona, Verona, Italy
    Search for more papers by this author
  • Eric Salmon,

    1. Cyclotron Research Centre and Department of Neurology, University of Liège, Liège, Belgium
    Search for more papers by this author
  • Patrick Santens,

    1. Department of Neurology, University Hospital Ghent and University of Ghent, Gent, Belgium
    Search for more papers by this author
  • Jean-Jacques Martin,

    1. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    Search for more papers by this author
  • Patrick Cras,

    1. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    2. Department of Neurology, Antwerp University Hospital, Edegem, Belgium
    Search for more papers by this author
  • Rik Vandenberghe,

    1. Laboratory for Cognitive Neurology, Department of Neurology, University of Leuven and University Hospitals Leuven Gasthuisberg, Leuven, Belgium
    Search for more papers by this author
  • Peter Paul De Deyn,

    1. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    2. Department of Neurology and Memory Clinic, Hospital Network Antwerp, Middelheim and Hoge Beuken, Antwerp, Belgium
    Search for more papers by this author
  • Marc Cruts,

    Corresponding author
    1. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    • Department of Molecular Genetics, VIB, Antwerp, Belgium
    Search for more papers by this author
  • Christine Van Broeckhoven,

    Corresponding author
    1. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
    • Department of Molecular Genetics, VIB, Antwerp, Belgium
    Search for more papers by this author
  • Julie van der Zee,

  • Ilse Gijselinck,

  • Lubina Dillen,

  • Tim Van Langenhove,

  • Jessie Theuns,

  • Stéphanie Philtjens,

  • Kristel Sleegers,

  • Veerle Bäumer,

  • Githa Maes,

  • Ellen Corsmit,

  • Marc Cruts,

  • Christine Van Broeckhoven,

  • Julie van der Zee,

  • Ilse Gijselinck,

  • Lubina Dillen,

  • Tim Van Langenhove,

  • Stéphanie Philtjens,

  • Jessie Theuns,

  • Kristel Sleegers,

  • Veerle Bäumer,

  • Githa Maes,

  • Marc Cruts,

  • Christine Van Broeckhoven,

  • Sebastiaan Engelborghs,

  • Peter P. De Deyn,

  • Patrick Cras,

  • Sebastiaan Engelborghs,

  • Peter P. De Deyn,

  • Mathieu Vandenbulcke,

  • Mathieu Vandenbulcke,

  • Barbara Borroni,

  • Alessandro Padovani,

  • Silvana Archetti,

  • Robert Perneczky,

  • Janine Diehl-Schmid,

  • Matthis Synofzik,

  • Walter Maetzler,

  • Jennifer Müller vom Hagen,

  • Ludger Schöls,

  • Matthis Synofzik,

  • Walter Maetzler,

  • Jennifer Müller vom Hagen,

  • Ludger Schöls,

  • Michael T. Heneka,

  • Frank Jessen,

  • Alfredo Ramirez,

  • Delia Kurzwelly,

  • Carmen Sachtleben,

  • Wolfgang Mairer,

  • Alexandre de Mendonça,

  • Gabriel Miltenberger-Miltenyi,

  • Sónia Pereira,

  • Clara Firmo,

  • José Pimentel,

  • Raquel Sanchez-Valle,

  • Albert Llado,

  • Anna Antonell,

  • Jose Molinuevo ,

  • Ellen Gelpi,

  • Caroline Graff,

  • Huei-Hsin Chiang,

  • Marie Westerlund,

  • Caroline Graff,

  • Anne Kinhult Ståhlbom,

  • Håkan Thonberg,

  • Inger Nennesmo,

  • Anne Börjesson-Hanson,

  • Benedetta Nacmias,

  • Silvia Bagnoli,

  • Sandro Sorbi,

  • Valentina Bessi,

  • Irene Piaceri,

  • Isabel Santana,

  • Beatriz Santiago,

  • Isabel Santana,

  • Maria Helena Ribeiro,

  • Maria Rosário Almeida,

  • Catarina Oliveira,

  • João Massano,

  • Carolina Garret,

  • Paula Pires,

  • Giovanni Frisoni,

  • Orazio Zanetti,

  • Cristian Bonvicini,

  • Stayko Sarafov,

  • Ivailo Tournev,

  • Albena Jordanova,

  • Ivailo Tournev,

  • Gabor G. Kovacs,

  • Thomas Ströbel,

  • Michael T. Heneka,

  • Frank Jessen,

  • Alfredo Ramirez,

  • Delia Kurzwelly,

  • Carmen Sachtleben,

  • Wolfgang Mairer;,

  • Frank Jessen,

  • Radoslav Matej,

  • Eva Parobkova,

  • Adrian Danel,

  • Thomas Arzberger,

  • Gian Maria Fabrizi,

  • Silvia Testi,

  • Sergio Ferrari,

  • Tiziana Cavallaro,

  • Eric Salmon,

  • Patrick Santens,

  • Patrick Cras,

  • on behalf of the European Early-Onset Dementia (EOD) Consortium

      Search for more papers by this author

    • Communicated by William Oetting

    • EOD Consortium members that contributed to the data in this article are listed in the appendix.

    • Contract grant sponsors: Interuniversity Attraction Poles (IAP) program P6/43 of the Belgian Science Policy Office; the Europe Initiative on Centers of Excellence in Neurodegeneration (CoEN); the Methusalem program supported by the Flemish Government; the Foundation for Alzheimer Research (SAO/FRMA); the Medical Foundation Queen Elisabeth; the Research Foundation Flanders (FWO); the Agency for Innovation by Science and Technology Flanders (IWT); the Special Research Fund of the University of Antwerp, Belgium; the Czech Ministry of Health (IGA NT 12094–5/2011); the Cassa di Risparmio PT e Pescia (n. 2011.0264); Fondazione CariVerona (2009.1026 “Cognitive and behavioral disability in Dementias and Psychosis”); Swedish Brain Power; Swedish Research Council; the King Gustaf V and Queen Victoria's Foundation of Freemasons; the foundations of Marianne and Marcus Wallenberg, Knut and Alice Wallenberg, Gun and Bertil Stohne, and Gamla tjänarinnor; Swedish Alzheimer Foundation.

    Correspondence to: Christine Van Broeckhoven, Neurodegenerative Brain Diseases Group, VIB Department of Molecular Genetics, University of Antwerp–CDE, Universiteitsplein 1, B-2610, Antwerp, Belgium. E-mail: christine.vanbroeckhoven@molgen.vib-ua.be; Marc Cruts, Neurodegenerative Brain Diseases Group, VIB Department of Molecular Genetics, University of Antwerp–CDE, Universiteitsplein 1, B-2610, Antwerp, Belgium. E-mail: marc.cruts@molgen.vib-ua.be

    ABSTRACT

    We assessed the geographical distribution of C9orf72 G4C2 expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7–24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the G4C2 repeat in C9orf72 expansion carriers (P < 0.001) with the most common indel creating one long contiguous imperfect G4C2 repeat, which is likely more prone to replication slippage and pathological expansion.

    Ancillary