SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

Rubino Elisa, Innocenzo Rainero, Adriano Chiò, Ekaterina Rogaeva, Daniela Galimberti, Pierpaola Fenoglio, Yakov Grinberg, Giancarlo Isaia, Andrea Calvo, Salvatore Gentile, Amalia Cecilia Bruni, Peter Henry George-Hyslop, Elio Scarpini, Salvatore Gallone, Lorenzo Pinessi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1556-1562
Number of pages7
JournalNeurology
Volume79
Issue number15
DOIs
Publication statusPublished - Oct 9 2012

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Fingerprint

Dive into the research topics of 'SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis'. Together they form a unique fingerprint.

Cite this