<h3>Objective:</h3> 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 (<i>SQSTM1</i>) 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 <i>SQSTM1</i> mutations in a dataset of unrelated patients with FTLD or ALS, in comparison with healthy controls and patients with Paget disease of bone (PDB). <h3>Methods:</h3> Promoter region and all exons of <i>SQSTM1</i> 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. <h3>Results:</h3> We identified 6 missense mutations in the coding region of <i>SQSTM1</i> 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 <i>SQSTM1</i> variants were found in patients with FTLD and patients with ALS, including 4 variations in the promoter region. <h3>Conclusions:</h3> <i>SQSTM1</i> 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.

SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis