title: ATNX2 is not a regulatory gene in Italian amyotrophic lateral sclerosis patients with C9ORF72 GGGGCC expansion.
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.
authors.affiliation: ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, Neurology II, University of Torino, Turin, Italy; Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy. Electronic address: achio@usa.net.
authors.forename: Adriano
authors.initials: A
authors.lastname: Chiò
authors.affiliation: Department of Neurological Rehabilitation, Fondazione Salvatore Maugeri, IRCCS, Istituto Scientifico di Milano, Milano, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Mora
authors.affiliation: Centro Clinico NEMO-Roma. Neurological Institute, Catholic University and I.C.O.M.M. Association for ALS Research, Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Sabatelli
authors.affiliation: Department of Neurosciences, Ophthalmology, Genetics, Rehabilitation, Maternal and Child Health, IRCCS Azienda Ospedaliero-Universitaria San Martino IST, Genoa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Caponnetto
authors.affiliation: NEuroMuscular Omnicenter, Serena Onlus Foundation, Milan, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Lunetta
authors.affiliation: Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Bryan J
authors.initials: BJ
authors.lastname: Traynor
authors.affiliation: Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Neurological Institute, Neuromuscular Center, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Janel O
authors.initials: JO
authors.lastname: Johnson
authors.affiliation: Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Mike A
authors.initials: MA
authors.lastname: Nalls
authors.affiliation: ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, Neurology II, University of Torino, Turin, Italy; Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Calvo
authors.affiliation: ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, Neurology II, University of Torino, Turin, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Moglia
authors.affiliation: Department of Neurology, Azienda Universitario Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Borghero
authors.affiliation: Department of Medical, Surgical Neurological Metabolic and Aging Sciences, Second University of Naples, Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Trojsi
authors.affiliation: ALS Clinical Research Center, Bio. Ne. C., University of Palermo, Palermo, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: La Bella
authors.affiliation: Neurorehabilitation Unit/ALS Center, Salvatore Maugeri Foundation, IRCCS, Scientific Institute of Mistretta, Mistretta, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Volanti
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Simone
authors.affiliation: Center for Diagnosis and Cure of Rare Diseases, Department of Neurology, IRCCS Institute of Neurological Sciences, Bologna, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Salvi
authors.affiliation: Neurological Clinic, Marche Polytechnic University, Ancona, Italy.
authors.forename: Francesco O
authors.initials: FO
authors.lastname: Logullo
authors.affiliation: Department of Neurology and Institute of Experimental Neurology (INSPE), IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Nilo
authors.initials: N
authors.lastname: Riva
authors.affiliation: Division of Genetics and Cell Biology, Unit of Genomics for human disease diagnosis, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Carrera
authors.affiliation: Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Giannini
authors.affiliation: Department of Neuroscience, S. Agostino- Estense Hospital, and University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Mandrioli
authors.affiliation: Department of Neurology, Santa Chiara Hospital, Trento, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Tanel
authors.affiliation: Department of Neurology, University of Chieti, Chieti, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Capasso
authors.affiliation: Neurology Unit, School of Medicine and Surgery and NeuroMI, University of Milano-Bicocca, Monza, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Tremolizzo
authors.affiliation: Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Battistini
authors.affiliation: Multiple Sclerosis Centre, ASL 8, Cagliari/Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Murru
authors.affiliation: Department of Neurosciences, Ophthalmology, Genetics, Rehabilitation, Maternal and Child Health, IRCCS Azienda Ospedaliero-Universitaria San Martino IST, Genoa, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Origone
authors.affiliation: Institute of Medical Genetics, Catholic University, Rome, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Zollino
authors.affiliation: Department of Laboratory Medicine, Medical Genetics, Niguarda Ca' Granda Hospital, Milan, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Penco
authors.affiliation: Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), 'Amedeo Avogadro' University of Eastern Piedmont, Novara, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Mazzini
authors.affiliation: ALS Center, Department of Neurology, Azienda Ospedaliera Universitaria Maggiore della Carità, Novara, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: D'Alfonso
authors.affiliation: ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, Neurology II, University of Torino, Turin, Italy; Department of Laboratory Medicine, Laboratory of Molecular Genetics, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Restagno
authors.affiliation: ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, Neurology II, University of Torino, Turin, Italy; Department of Laboratory Medicine, Laboratory of Molecular Genetics, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Brunetti
authors.affiliation: ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, Neurology II, University of Torino, Turin, Italy; Department of Laboratory Medicine, Laboratory of Molecular Genetics, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza, Torino, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Barberis
authors.affiliation: Institute of Neurological Sciences, National Research Council, Mangone, Cosenza, Italy.
authors.forename: Francesca L
authors.initials: FL
authors.lastname: Conforti
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000067698:Ataxin-2 / Q000235:genetics*; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D011506:Proteins / Q000235:genetics*
chemical_list: C000593752:ATXN2 protein, human; D000067698:Ataxin-2; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins
keywords: ATXN2; Amyotrophic lateral sclerosis; C9ORF72; Phenotype