J Neurol Neurosurg Psychiatry 84:183-187 doi:10.1136/jnnp-2012-303433
  • Neurogenetics
  • Research paper

Ubiquilin 2 mutations in Italian patients with amyotrophic lateral sclerosis and frontotemporal dementia

  1. The SLAGEN Consortium
  1. 1Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’, Milan, Italy
  2. 2Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy
  3. 3Doctoral School in Molecular Medicine, University of Milan, Milan, Italy
  4. 4IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
  5. 5Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, ‘Dino Ferrari’ Center, Università degli Studi di Milano, Milan, Italy
  6. 6Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases, ‘A. Avogadro’ University, Novara, Italy
  7. 7Department of Neuroscience, University of Padua, Padua, Italy
  8. 8Laboratory of Experimental Neurobiology, IRCCS National Neurological Institute ‘C. Mondino’, Pavia, Italy
  9. 9Department of Neurological Sciences, University of Pavia, Pavia, Italy
  10. 10Research Consortium ‘Luigi Amaducci’ CRIC, Arcugnano (Vicenza), Italy
  11. 11Department of Neurology, A. Avogadro University and Maggiore della Carita Hospital, Novara, Italy
  1. Correspondence to Professor Vincenzo Silani, Department of Neurology, Università degli Studi di Milano, IRCCS Istituto Auxologico Italiano, Piazzale Brescia 20, Milan 20149, Italy; vincenzo{at}
  • Received 10 June 2012
  • Revised 24 September 2012
  • Accepted 25 September 2012
  • Published Online First 8 November 2012


Objectives Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease mainly involving cortical and spinal motor neurones. Molecular studies have recently identified different mutations in the  ubiquilin-2 (UBQLN2) gene as causative of a familial form of X-linked ALS, 90% penetrant in women. The aim of our study was to analyse the UBQLN2 gene in a large cohort of patients with familial (FALS) and sporadic (SALS) amyotrophic lateral sclerosis, with or without frontotemporal dementia (FTD), and in patients with FTD.

Methods We analysed the UBQLN2 gene in 819 SALS cases, 226 FALS cases, 53 ALS–FTD patients, and 63 patients with a clinical record of FTD. Molecular analysis of the entire coding sequence was carried out in all FALS and ALS–FTD patients, while SALS and FTD patients were analysed specifically for the genomic region coding for the PXX repeat tract. Healthy controls were 845 anonymous blood donors and were screened for the PXX repeat region only.

Results We found five different variants in the UBQLN2 gene in five unrelated ALS patients. Three variants, including two novel ones, involved a proline residue in the PXX repeat region and were found in three FALS cases. The other two were novel variants, identified in one FALS and one SALS patient. None of these variants was present in controls, while one control carried a new heterozygous variant.

Conclusions Our data support the role of the UBQLN2 gene in the pathogenesis of FALS, being conversely a rare genetic cause in SALS even when complicated by FTD.

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