title: SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
abstract: 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.
authors.affiliation: Neurology II, Department of Internal Medicine, University of Torino, Torino, Italy. elisa.rubino@unito.it
authors.forename: Elisa
authors.initials: E
authors.lastname: Rubino
authors.forename: Innocenzo
authors.initials: I
authors.lastname: Rainero
authors.forename: Adriano
authors.initials: A
authors.lastname: Chiò
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Rogaeva
authors.forename: Daniela
authors.initials: D
authors.lastname: Galimberti
authors.forename: Pierpaola
authors.initials: P
authors.lastname: Fenoglio
authors.forename: Yakov
authors.initials: Y
authors.lastname: Grinberg
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Isaia
authors.forename: Andrea
authors.initials: A
authors.lastname: Calvo
authors.forename: Salvatore
authors.initials: S
authors.lastname: Gentile
authors.forename: Amalia Cecilia
authors.initials: AC
authors.lastname: Bruni
authors.forename: Peter Henry
authors.initials: PH
authors.lastname: St George-Hyslop
authors.forename: Elio
authors.initials: E
authors.lastname: Scarpini
authors.forename: Salvatore
authors.initials: S
authors.lastname: Gallone
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Pinessi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000473:pathology; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011401:Promoter Regions, Genetic; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein