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Analysis of the C9orf72 Gene in Patients with Amyotrophic Lateral Sclerosis in Spain and Different Populations Worldwide

Authors

  • Alberto García-Redondo,

    1. Department of Neurology, ALS Unit, Instituto de Investigación Biomédica Hospital 12 de Octubre, Madrid, Spain
    2. Centre for Biomedical Network Research on Rare Diseases (CIBERER), Valencia, Spain
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    • These authors contributed equally to this work.

  • Oriol Dols-Icardo,

    1. Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
    2. Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
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    • These authors contributed equally to this work.

  • Ricard Rojas-García,

    1. Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
    2. Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
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  • Jesús Esteban-Pérez,

    1. Department of Neurology, ALS Unit, Instituto de Investigación Biomédica Hospital 12 de Octubre, Madrid, Spain
    2. Centre for Biomedical Network Research on Rare Diseases (CIBERER), Valencia, Spain
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  • Pilar Cordero-Vázquez BS,

    1. Department of Neurology, ALS Unit, Instituto de Investigación Biomédica Hospital 12 de Octubre, Madrid, Spain
    2. Centre for Biomedical Network Research on Rare Diseases (CIBERER), Valencia, Spain
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  • José Luis Muñoz-Blanco,

    1. Department of Neurology, ALS Unit, Hospital Universita rio Gregorio Marañón, Madrid, Spain
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  • Irene Catalina,

    1. Department of Neurology, ALS Unit, Hospital Universita rio Gregorio Marañón, Madrid, Spain
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  • Miguel González-Muñoz,

    1. Department of Immunology, ALS Unit, Hospital Carlos III, Madrid, Spain
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  • Luis Varona,

    1. Department of Neurology and Department of Genetics, Hospital Universitario Basurto, Bilbao, Spain
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  • Esther Sarasola,

    1. Department of Neurology and Department of Genetics, Hospital Universitario Basurto, Bilbao, Spain
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  • Monica Povedano,

    1. Department of Neurology, Hospital de Bellvitge, Barcelona, Spain
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  • Teresa Sevilla,

    1. Department of Neurology, Hospital de la Fe, Valencia, Spain
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  • Antonio Guerrero,

    1. ALS Unit, Hospital Clínico Universitario “San Carlos”, Madrid, Spain
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  • Julio Pardo,

    1. Department of Neurology, Clinical Hospital of Santiago de Compostela, SERGAS, Santiago de Compostela, Spain
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  • Adolfo López de Munain,

    1. Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
    2. Department of Neurology, Hospital Universitario Donostia, Donostia-San Sebastián, Neuroscience Area, Biodonostia Health Research Institut, San Sebastián, Spain
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  • Celedonio Márquez-Infante,

    1. Department of Neurology, Hospital Universitario Virgen del Rocío, Sevilla, Spain
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  • Francisco Javier Rodríguez de Rivera,

    1. Department of Neurology, ALS Unit, Hospital Universitario La Paz, Madrid, Spain
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  • Pau Pastor,

    1. Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
    2. Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, and Department of Neurology, Clínica Universidad de Navarra, University of Navarra Medical School, Pamplona, Spain
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  • Ivonne Jericó,

    1. Department of Neurology, Complejo Hospitalario de Navarra, Pamplona, Spain
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  • Amaya Álvarez de Arcaya,

    1. Department of Neurology, Hospital Universitario Araba-Txagorritxu, Vitoria-Gasteiz, Spain
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  • Jesús S. Mora,

    1. Department of Neurology, ALS Unit, Hospital Carlos III, Madrid, Spain
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  • Jordi Clarimón,

    Corresponding author
    1. Center for Networker Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
    • Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
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  • The C9ORF72 Spanish Study Group,

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    • The members of The C9ORF72 Spanish Study Group are listed in the Appendix.

  • Juan Francisco Gonzalo-Martínez,

  • Alexandra Juárez-Rufián,

  • Gabriela Atencia,

  • Rosario Jiménez-Bautista,

  • Yolanda Morán,

  • Javier Mascías,

  • María Hernández-Barral,

  • Solange Kapetanovic,

  • María García-Barcina,

  • Carmen Alcalá,

  • Álvaro Vela,

  • Concepción Ramírez-Ramos,

  • Lucía Galán,

  • Jordi Pérez-Tur,

  • Beatriz Quintáns,

  • M Jesús Sobrido,

  • Roberto Fernández-Torrón,

  • Juan José Poza,

  • Ana Gorostidi,

  • Carmen Paradas,

  • Pablo Villoslada,

  • Pilar Larrodé,

  • José Luis Capablo,

  • Jordi Pascual-Calvet,

  • Miguel Goñi,

  • Yolanda Morgado,

  • Miriam Guitart,

  • Sira Moreno-Laguna,

  • Almudena Rueda,

  • Carlos Martín-Estefanía,

  • Carlos Cemillán,

  • Rafael Blesa,

  • Alberto Lleó


  • Contract grant sponsors: Neuromuscular Database Project, CIBERNED (PI 2010/11); MICINN (SAF2010-10434); ISCIII (PI10/00092 and EC08/00049).

  • Communicated by William S. Oetting

Correspondence to: Jordi Clarimón, Neurology Department, Hospital de la Santa Creu i Sant Pau, Sant Antoni M. Claret 167, 08025 Barcelona, Spain. E-mail: jclarimon@santpau.cat

ABSTRACT

A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) can cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). We assessed its frequency in 781 sporadic ALS (sALS) and 155 familial ALS (fALS) cases, and in 248 Spanish controls. We tested the presence of the reported founder haplotype among mutation carriers and in 171 Ceph Europeans from Utah (CEU), 170 Yoruba Africans, 81 Han Chinese, and 85 Japanese subjects. The C9orf72 expansion was present in 27.1% of fALS and 3.2% of sALS. Mutation carriers showed lower age at onset (P = 0.04), shorter survival (P = 0.02), greater co-occurrence of FTD (P = 8.2 × 10−5), and more family history of ALS (P = 1.4 × 10−20), than noncarriers. No association between alleles within the normal range and the risk of ALS was found (P = 0.12). All 61 of the mutation carriers were tested and a patient carrying 28 hexanucleotide repeats presented with the founder haplotype. This haplotype was found in 5.6% Yoruba Africans, 8.9% CEU, 3.9% Japanese, and 1.6% Han Chinese chromosomes.

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