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

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease mainly involving cortical and spinal motor neurons. Recently, molecular studies identified different mutations in ubiquilin-2 (UBQLN2) gene as causative of a familial form of X-linked ALS, 90% penetrant in females. Aim of our study was to analyze the UBQLN2 gene in a large cohort of familial and sporadic ALS patients, with or without frontotemporal dementia (FTD), and in patients with FTD only. We analyzed the UBQLN2 gene in 819 sporadic ALS cases (SALS), 226 familial ALS cases (FALS), 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 analyzed 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. We found five different variants in the UBQLN2 gene in five unrelated ALS patients. Three of them, 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 were present in controls, while one control carried a new heterozygous variant. Our data support the role of UBQLN2 gene in the pathogenesis of FALS, being conversely a rare genetic cause in SALS even when complicated by FTD.