title: Six SQSTM1 mutations in a Chinese amyotrophic lateral sclerosis cohort.
abstract: The purpose of this study was to identify SQSTM1 gene mutations, estimate survival based on the progression rate of the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) score (ΔFS), and characterize the relationships between SQSTM1 mutations and clinical phenotypes in Chinese ALS patients. We sequenced the SQSTM1 gene in 35 familial ALS patients, 436 sporadic ALS patients, and 384 healthy controls. SQSTM1 gene mutations were screened with PCR and direct sequencing; the correlations between genotype and phenotype and the progressive ALSFRS-R ratio were analyzed. Results revealed six heterozygous missense mutations in 471 ALS patients: c.241 G> A (p.E81K), c.717 C> A (p.N239K), c.889 G> A (p.G297S), c.1116 G> C (p.E372D), c.1162 C> T (p.P388S) and c.1175 C> T (p.P392 L). The gender ratio was 1:1, and the limb was the site of disease onset in mutation-positive patients. Notably, the ΔFS analysis revealed that the risk of death or tracheostomy was significantly increased in SQSTM1 mutation carriers (p < 0.05). In conclusion, E81K, N239K, G297S, E372D, P388S and P392 L were detected in the PB1, TRAF6, PEST and UBA domains, which are important to p62 function and prone to ALS. The incidence of ALS caused by the SQSTM1 mutation has increased from 30 to 35 worldwide.
authors.affiliation: a Department of Neurology , Peking University Third Hospital , Haidian District, Beijing , China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: a Department of Neurology , Peking University Third Hospital , Haidian District, Beijing , China.
authors.forename: Lu
authors.initials: L
authors.lastname: Tang
authors.affiliation: a Department of Neurology , Peking University Third Hospital , Haidian District, Beijing , China.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Pan
authors.affiliation: b Department of Molecular Life Sciences , Tokai University School of Medicine , Isehara , Kanagawa , Japan.|c The Institute of Medical Sciences, Tokai University , Isehara , Kanagawa , Japan.|e Research Center for Brain and Nervous Diseases, Tokai University Graduate School of Medicine , Isehara , Kanagawa , Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Hadano
authors.affiliation: a Department of Neurology , Peking University Third Hospital , Haidian District, Beijing , China.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Fan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D000071456:Sequestosome-1 Protein; D012720:Severity of Illness Index
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein
keywords: Amyotrophic lateral sclerosis; SQSTM1 gene; clinical features; mutation