ATNX2 is not a regulatory gene in Italian amyotrophic lateral sclerosis patients with C9ORF72 GGGGCC expansion

Adriano Chiò, Gabriele Mora, M. Sabatelli, Claudia Caponnetto, Christian Lunetta, Bryan J. Traynor, Janel O. Johnson, Mike A. Nalls, Andrea Calvo, C. Moglia, Giuseppe Borghero, F. Trojsi, V. La Bella, Paolo Volanti, I. L. Simone, Fabrizio Salvi, F. Logullo, Nilo Riva, Paola Carrera, Fabio GianniniJessica Mandrioli, Raffaella Tanel, Margherita Capasso, Lucio Tremolizzo, Stefania Battistini, Maria Rita Murru, Paola Origone, Marcella Zollino, S. Penco, Letizia Mazzini, Sandra D'Alfonso, Gabriella Restagno, Maura Brunetti, Marco Barberis, Francesca Luisa Conforti, Giancarlo Logroscino, Ilaria Bartolomei, Giovanni L. Mancardi, Paola Mandich, Kalliopi Marinou Aktipi, Riccardo Sideri, Lorena Mosca, Giuseppe Lauria, M. Corbo, Nicola Fini, Antonio Fasano, Alessandro Arosio, Carlo Ferrarese, G. Tedeschi, Maria Rosaria Monsurrò, G. Piccirillo, Cinzia Femiano, Anna Bersano, Lucia Corrado, Alessandra Bagarotti, Rossella Spataro, Tiziana Colletti, Amelia Conte, Marco Luigetti, Serena Lattante, Giuseppe Marangi, Marialuisa Santarelli, Antonio Petrucci, Claudia Ricci, Michele Benigni, Federico Casale, Giuseppe Marrali, Giuseppe Fuda, Irene Ossola, Stefania Cammarosano, Antonio Ilardi, Umberto Manera, Davide Bertuzzo, Raffaella Tanel, Fabrizio Pisano, Emanuela Costantino, Carla Pani, Roberta Puddu, Carla Caredda, Valeria Piras, Stefania Tranquilli, Stefania Cuccu, Daniela Corongiu, Maurizio Melis, Antonio Milia, Francesco Marrosu, M. G. Marrosu, Gianluca Floris, Antonino Cannas, Stefania Cuccu, Stefania Tranquilli, Anna Ticca, Maura Pugliatti, Angelo Pirisi, Leslie D. Parish, Patrizia Occhineri, Enzo Ortu, Tea B. Cau, Daniela Loi

Research output: Contribution to journalArticle

Abstract

There are indications that both familial amyotrophic lateral sclerosis (ALS) and sporadic ALS phenotype and prognosis are partly regulated by genetic and environmental factors, supporting the theory that ALS is a multifactorial disease. The aim of this article was to assess the role of ATXN2 intermediate length repeats in a large series of Italian and Sardinian ALS patients and controls carrying a pathogenetic C9ORF72 GGGGCC hexanucleotide repeat. A total of 1972 ALS cases were identified through the database of the Italian ALS Genetic consortium, a collaborative effort including 18 ALS centers throughout Italy. The study population included: (1) 276 Italian and 57 Sardinian ALS cases who carried the C9ORF72 expansion; (2) 1340 Italian and 299 Sardinian ALS cases not carrying the C9ORF72 expansion. A total of healthy 1043 controls were also assessed. Most Italian and Sardinian cases and controls were homozygous for 22/22 or 23/23 repeats or heterozygous for 22/23 repeats of the ATXN2 gene. ATXN2 intermediate length repeats alleles (≥28) were detected in 3 (0.6%) Italian ALS cases carrying the C9ORF72 expansion, in none of the Sardinian ALS cases carrying the expansion, in 60 (4.3%) Italian cases not carrying the expansion, and in 6 (2.0%) Sardinian ALS cases without C9ORF72 expansion. Intermediate length repeat alleles were found in 12 (1.5%) Italian controls and 1 (0.84%) Sardinian controls. Therefore, ALS patients with C9ORF72 expansion showed a lower frequency of ATXN2 polyQ intermediate length repeats than both controls (Italian cases, p = 0.137; Sardinian cases, p = 0.0001) and ALS patients without C9ORF72 expansion (Italian cases, p = 0.005; Sardinian cases, p = 0.178). In our large study on Italian and Sardinian ALS patients with C9ORF72 GGGGCC hexanucleotide repeat expansion, compared to age-, gender- and ethnic-matched controls, ATXN2 polyQ intermediate length does not represent a modifier of ALS risk, differently from non-C9ORF72 mutated patients.

Original languageEnglish
Pages (from-to)218.e5-218.e8
JournalNeurobiology of Aging
Volume39
DOIs
Publication statusPublished - Mar 1 2016

Keywords

  • Amyotrophic lateral sclerosis
  • ATXN2
  • C9ORF72
  • Phenotype

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Ageing
  • Developmental Biology
  • Geriatrics and Gerontology

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  • Cite this

    Chiò, A., Mora, G., Sabatelli, M., Caponnetto, C., Lunetta, C., Traynor, B. J., Johnson, J. O., Nalls, M. A., Calvo, A., Moglia, C., Borghero, G., Trojsi, F., La Bella, V., Volanti, P., Simone, I. L., Salvi, F., Logullo, F., Riva, N., Carrera, P., ... Loi, D. (2016). ATNX2 is not a regulatory gene in Italian amyotrophic lateral sclerosis patients with C9ORF72 GGGGCC expansion. Neurobiology of Aging, 39, 218.e5-218.e8. https://doi.org/10.1016/j.neurobiolaging.2015.11.027