期刊
NEUROLOGY
卷 79, 期 15, 页码 1556-1562出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1212/WNL.0b013e31826e25df
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资金
- Ministero dell'Istruzione, dell'Universita e della Ricerca Scientifica (MIUR) of Italy
- Regione Piemonte (Italy)
- Italian Ministry of Health (Ricerca Finalizzata and CCM grants)
- Regione Piemonte (Ricerca Finalizzata)
- Italian Ministry of University and Research
- University of Torino
- Fondazione Vialli e Mauro for ALS Research
- ONLUS
- Compagnia San Paolo
- Federazione Italiana Giuoco Calcio
- European Commission [259867]
- W. Garfield Weston Foundation
- Canadian Institutes of Health Research
- Ontario Research Fund
- Fondazione Mondino
- Regione Piemonte and Compagnia di San Paolo
- Assessorato alla Salute-Regione Calabria
- Associazione per la Ricerca Neurogenetica Onlus
- Howard Hughes Medical Institute
- Wellcome Trust
- Alzheimer Society of Ontario
- Canada Foundation for Innovation
- Ontario Mental Health Foundation
- Genome Canada
- Alzheimer Society of Canada
Objective: There is increasing evidence that common genetic risk factors underlie frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Recently, mutations in the sequestosome 1 (SQSTM1) gene, which encodes p62 protein, have been reported in patients with ALS. P62 is a multifunctional adapter protein mainly involved in selective autophagy, oxidative stress response, and cell signaling pathways. The purpose of our study was to evaluate the frequency of SQSTM1 mutations in a dataset of unrelated patients with FTLD or ALS, in comparison with healthy controls and patients with Paget disease of bone (PDB). Methods: Promoter region and all exons of SQSTM1 were sequenced in a large group of subjects, including patients with FTLD or ALS, healthy controls, and patients with PDB. The clinical characteristics of patients with FTLD or ALS with gene mutations were examined. Results: We identified 6 missense mutations in the coding region of SQSTM1 in patients with either FTLD or ALS, none of which were found in healthy controls or patients with PDB. In silico analysis suggested a pathogenetic role for these mutations. Furthermore, 7 novel noncoding SQSTM1 variants were found in patients with FTLD and patients with ALS, including 4 variations in the promoter region. Conclusions: SQSTM1 mutations are present in patients with FTLD and patients with ALS. Additional studies are warranted in order to better investigate the role of p62 in the pathogenesis of both FTLD and ALS. Neurology (R) 2012; 79: 1556-1562
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