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:

Sequestosome-1 (SQSTM1) sequence variants in ALS cases in the UK: prevalence and coexistence of SQSTM1 mutations in ALS kindred with PDB

“…In contrast to the findings of Rubino et al 4 we found no significant differences in allelic and genotypic frequencies of the p.(Glu274Asp) or other synonymous variants between our ALS cohorts and controls derived from a UK control cohort and publically available databases. In contrast, the properties of the p.(Pro392Leu) and p.(Glu155Lys) mutations are more likely to contribute pathogenic effects.…”

“…Analysis of all SQSTM1 variants that are predicted as being pathogenic in published cohorts, [3][4][5][6] and the current study demonstrated that pathogenic SQSTM1 variants are significantly associated with FALS with a combined odds ratio of 3.91 (P MH ¼ 0.0002, Supplementary Table 1). No significant association was found for SALS cases.…”

“…We screened all eight coding exons of the SQSTM1 gene (NM_003900.4) ( Figure 1a The c.822G4C (rs55793208, p.(Glu274Asp)) substitution has been previously reported in ALS by Rubino et al 4 and results in a SQSTM1 mutations in ALS CT Kwok et al glutamate to aspartate change in the PEST domain of SQSTM1. All three synonymous variants have been previously reported, but not in ALS.…”

“…[3][4][5][6] However, because of lack of DNA in multiple members of FALS kindred, to date it has not been proved that any of these mutations are transmitted with disease in ALS. Nevertheless, among the coding mutations is p.(Pro392Leu), which is common in Paget's disease of bone (PDB), 7,8 where there is evidence of transmission of the mutation with disease in multiple kindred.…”

Neuroimaging Correlates of Frontotemporal Dementia Associated with SQSTM1 Mutations

“…This is a multicenter retrospective and exploratory collaborative study in which all the members of the EU EOD consortium [10] and other authors of published studies analyzing the SQSTM1 gene [10,11] were asked to provide available brain MRI scans from the subjects screened in previous studies whether they were FTD/SQSTM1 carriers or not. A subject was considered to be a FTD/SQSTM1 carrier when she/he fulfilled research criteria for FTLD [12] and carried a disease-segregating SQSTM1 genetic variant or, if DNA samples from relatives to demonstrate familial segregation were unavailable, their SQSTM1 variant, was only found in FTLD cases or the variants were more frequent among the cases [9,11].…”