. 2015 Oct;36(10):2906.e1-5.

doi: 10.1016/j.neurobiolaging.2015.06.013. Epub 2015 Jun 25.

ATXN2 is a modifier of phenotype in ALS patients of Sardinian ancestry

Giuseppe Borghero¹, Maura Pugliatti², Francesco Marrosu¹, Maria Giovanna Marrosu³, Maria Rita Murru³, Gianluca Floris¹, Antonino Cannas¹, Leslie D Parish², Tea B Cau⁴, Daniela Loi⁴, Anna Ticca⁵, Sebastiano Traccis⁶, Umberto Manera⁷, Antonio Canosa⁸, Cristina Moglia⁷, Andrea Calvo⁹, Marco Barberis¹⁰, Maura Brunetti¹⁰, Alan E Renton¹¹, Mike A Nalls¹², Bryan J Traynor¹³, Gabriella Restagno¹⁴, Adriano Chiò¹⁵; ITALSGEN and SARDINALS consortia

Collaborators, Affiliations

Collaborators

ITALSGEN and SARDINALS consortia:
Francesco O Logullo, Isabella Simone, Giancarlo Logroscino, Fabrizio Salvi, Ilaria Bartolomei, Margherita Capasso, Claudia Caponnetto, Gianluigi Mancardi, Paola Mandich, Paola Origone, Francesca L Conforti, Gabriele Mora, Kalliopi Marinou, Riccardo Sideri, Christian Lunetta, Silvana Penco, Lorena Mosca, Riva Nilo, Giuseppe Lauria Pinter, Massimo Corbo, Paolo Volanti, Jessica Mandrioli, Nicola Fini, Eleni Georgoulopoulou, Lucio Tremolizzo, Maria Rosaria, Gioacchino Tedeschi, Viviana Cristillo, Vincenzo la Bella, Rossella Spataro, Tiziana Colletti, Mario Sabatelli, Marcella Zollino, Amelia Conte, Marco Luigetti, Serena Lattante, Giuseppe Marangi, Marialuisa Santarelli, Antonio Petrucci, Fabio Giannini, Stefania Battistini, Claudia Ricci, Federico Casale, Giuseppe Marrali, Giuseppe Fuda, Irene Ossola, Stefania Cammarosano, Antonio Ilardi, 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, Anna Ticca, Angelo Pirisi, Patrizia Occhineri, Enzo Ortu

Affiliations

¹ Department of Neurology, Azienda Universitario Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy.
² Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
³ Multiple Sclerosis Center Laboratory, University of Cagliari, Cagliari, Italy.
⁴ Azienda Sanitaria Locale n. 2, Olbia-Tempio, Italy.
⁵ Department of Neurology, Azienda Ospedaliera San Francesco, Nuoro, Italy.
⁶ Department of Neurology, Ospedale Antonio Segni, Ozieri, Italy.
⁷ ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy.
⁸ ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy; Department of Neurosciences, Ophthalmology, Genetics, Rehabilitation and Child Health, University of Genoa, Genoa, Italy.
⁹ ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy; Neurology II, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
¹⁰ ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy; Laboratory of Molecular Genetics, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
¹¹ Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, USA.
¹² Molecular Genetics Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, USA.
¹³ Laboratory of Molecular Genetics, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy; Brain Science Institute, Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
¹⁴ Laboratory of Molecular Genetics, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
¹⁵ ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy; Neurology II, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy; Neuroscience Institute of Torino (NIT), Turin, Italy. Electronic address: achio@usa.net.

PMID: 26208502
PMCID: PMC5193218
DOI: 10.1016/j.neurobiolaging.2015.06.013

ATXN2 is a modifier of phenotype in ALS patients of Sardinian ancestry

Giuseppe Borghero et al. Neurobiol Aging. 2015 Oct.

. 2015 Oct;36(10):2906.e1-5.

doi: 10.1016/j.neurobiolaging.2015.06.013. Epub 2015 Jun 25.

Authors

Collaborators

ITALSGEN and SARDINALS consortia:
Francesco O Logullo, Isabella Simone, Giancarlo Logroscino, Fabrizio Salvi, Ilaria Bartolomei, Margherita Capasso, Claudia Caponnetto, Gianluigi Mancardi, Paola Mandich, Paola Origone, Francesca L Conforti, Gabriele Mora, Kalliopi Marinou, Riccardo Sideri, Christian Lunetta, Silvana Penco, Lorena Mosca, Riva Nilo, Giuseppe Lauria Pinter, Massimo Corbo, Paolo Volanti, Jessica Mandrioli, Nicola Fini, Eleni Georgoulopoulou, Lucio Tremolizzo, Maria Rosaria, Gioacchino Tedeschi, Viviana Cristillo, Vincenzo la Bella, Rossella Spataro, Tiziana Colletti, Mario Sabatelli, Marcella Zollino, Amelia Conte, Marco Luigetti, Serena Lattante, Giuseppe Marangi, Marialuisa Santarelli, Antonio Petrucci, Fabio Giannini, Stefania Battistini, Claudia Ricci, Federico Casale, Giuseppe Marrali, Giuseppe Fuda, Irene Ossola, Stefania Cammarosano, Antonio Ilardi, 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, Anna Ticca, Angelo Pirisi, Patrizia Occhineri, Enzo Ortu

Affiliations

¹ Department of Neurology, Azienda Universitario Ospedaliera di Cagliari and University of Cagliari, Cagliari, Italy.
² Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
³ Multiple Sclerosis Center Laboratory, University of Cagliari, Cagliari, Italy.
⁴ Azienda Sanitaria Locale n. 2, Olbia-Tempio, Italy.
⁵ Department of Neurology, Azienda Ospedaliera San Francesco, Nuoro, Italy.
⁶ Department of Neurology, Ospedale Antonio Segni, Ozieri, Italy.
⁷ ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy.
⁸ ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy; Department of Neurosciences, Ophthalmology, Genetics, Rehabilitation and Child Health, University of Genoa, Genoa, Italy.
⁹ ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy; Neurology II, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
¹⁰ ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy; Laboratory of Molecular Genetics, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
¹¹ Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, USA.
¹² Molecular Genetics Section, Laboratory of Neurogenetics, National Institute of Aging, Bethesda, USA.
¹³ Laboratory of Molecular Genetics, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy; Brain Science Institute, Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
¹⁴ Laboratory of Molecular Genetics, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
¹⁵ ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy; Neurology II, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy; Neuroscience Institute of Torino (NIT), Turin, Italy. Electronic address: achio@usa.net.

PMID: 26208502
PMCID: PMC5193218
DOI: 10.1016/j.neurobiolaging.2015.06.013

Abstract

Intermediate-length CAG expansions (encoding 27-33 glutamines, polyQ) of the Ataxin2 (ATXN2) gene represent a risk factor for amyotrophic lateral sclerosis (ALS). Recently, it has been proposed that ≥31 CAG expansions may influence ALS phenotype. We assessed whether ATXN2 intermediate-length polyQ expansions influence ALS phenotype in a series of 375 patients of Sardinian ancestry. Controls were 247 neurologically healthy subjects, resident in the study area, age- and gender-matched to cases. The frequency of ≥31 polyQ ATNX2 repeats was significantly more common in ALS cases (4 patients vs. no control, p = 0.0001). All patients with ≥31 polyQ repeats had a spinal onset versus 73.3% of patients with <31 polyQ repeats. Patients with an increased number of polyQ repeats have a shorter survival than those with <31 repeats (1.2 vs. 4.2 years, p = 0.035). In this large series of ALS patients of Sardinian ancestry, we have found that ≥31 polyQ repeats of the ATXN2 gene influenced patients' phenotype, being associated to a spinal onset and a significantly shorter survival.

Keywords: Amyotrophic lateral sclerosis; Ataxin 2 gene; Genetic modifier.

PubMed Disclaimer

Conflict of interest statement

statement All other authors report no conflicts of interest.

Figures

**Fig. 1**
Distribution of ATXN2 polyQ repeat lengths in amyotrophic lateral sclerosis (ALS) and control cases. In the insert, data bout cases and controls with ≥27 repeats are magnified. PolyQ lengths ≥31 are significantly more frequent in ALS cases (p = 0.0001) (red, ALS patients; blue, controls).

**Fig. 2**
Kaplan-Meier survival estimation from onset to death and/or tracheostomy. Blue line, <31 polyQ repeats; green line, ≥31 polyQ repeats. p = 0.035.

See this image and copyright information in PMC

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ATXN2 is a modifier of phenotype in ALS patients of Sardinian ancestry

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ATXN2 is a modifier of phenotype in ALS patients of Sardinian ancestry

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