title: SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis.
abstract: BACKGROUND
  The SQSTM1 gene encodes p62, a major pathologic protein involved in neurodegeneration.
  
  
  OBJECTIVE
  To examine whether SQSTM1 mutations contribute to familial and sporadic amyotrophic lateral sclerosis (ALS).
  
  
  METHODS
  Case-control study.
  
  
  METHODS
  Academic research. Patients  A cohort of 546 patients with familial (n = 340) or sporadic (n = 206) ALS seen at a major academic referral center were screened for SQSTM1 mutations.
  
  
  METHODS
  We evaluated the distribution of missense, deletion, silent, and intronic variants in SQSTM1 among our cohort of patients with ALS. In silico analysis of variants was performed to predict alterations in p62 structure and function.
  
  
  RESULTS
  We identified 10 novel SQSTM1 mutations (9 heterozygous missense and 1 deletion) in 15 patients (6 with familial ALS and 9 with sporadic ALS). Predictive in silico analysis classified 8 of 9 missense variants as pathogenic.
  
  
  CONCLUSIONS
  Using candidate gene identification based on prior biological knowledge and the functional prediction of rare variants, we identified several novel SQSTM1 mutations in patients with ALS. Our findings provide evidence of a direct genetic role for p62 in ALS pathogenesis and suggest that regulation of protein degradation pathways may represent an important therapeutic target in motor neuron degeneration.
authors.affiliation: Division of Neuromuscular Medicine, Ken and Ruth Davee Department of Neurology and Clinical Neurological Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Faisal
authors.initials: F
authors.lastname: Fecto
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yan
authors.forename: S Pavan
authors.initials: SP
authors.lastname: Vemula
authors.forename: Erdong
authors.initials: E
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Wenjie
authors.initials: W
authors.lastname: Chen
authors.forename: Jian Guo
authors.initials: JG
authors.lastname: Zheng
authors.forename: Yong
authors.initials: Y
authors.lastname: Shi
authors.forename: Nailah
authors.initials: N
authors.lastname: Siddique
authors.forename: Hasan
authors.initials: H
authors.lastname: Arrat
authors.forename: Sandra
authors.initials: S
authors.lastname: Donkervoort
authors.forename: Senda
authors.initials: S
authors.lastname: Ajroud-Driss
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sufit
authors.forename: Scott L
authors.initials: SL
authors.lastname: Heller
authors.forename: Han-Xiang
authors.initials: HX
authors.lastname: Deng
authors.forename: Teepu
authors.initials: T
authors.lastname: Siddique
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein