title: Exome sequencing to identify de novo mutations in sporadic ALS trios.
abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease whose causes are still poorly understood. To identify additional genetic risk factors, we assessed the role of de novo mutations in ALS by sequencing the exomes of 47 ALS patients and both of their unaffected parents (n = 141 exomes). We found that amino acid-altering de novo mutations were enriched in genes encoding chromatin regulators, including the neuronal chromatin remodeling complex (nBAF) component SS18L1 (also known as CREST). CREST mutations inhibited activity-dependent neurite outgrowth in primary neurons, and CREST associated with the ALS protein FUS. These findings expand our understanding of the ALS genetic landscape and provide a resource for future studies into the pathogenic mechanisms contributing to sporadic ALS.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California, USA. chesi@stanford.edu
authors.forename: Alessandra
authors.initials: A
authors.lastname: Chesi
authors.forename: Brett T
authors.initials: BT
authors.lastname: Staahl
authors.forename: Ana
authors.initials: A
authors.lastname: Jovičić
authors.forename: Julien
authors.initials: J
authors.lastname: Couthouis
authors.forename: Maria
authors.initials: M
authors.lastname: Fasolino
authors.forename: Alya R
authors.initials: AR
authors.lastname: Raphael
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Laura
authors.initials: L
authors.lastname: Elias
authors.forename: Meraida
authors.initials: M
authors.lastname: Polak
authors.forename: Crystal
authors.initials: C
authors.lastname: Kelly
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Williams
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Fifita
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Maragakis
authors.forename: Garth A
authors.initials: GA
authors.lastname: Nicholson
authors.forename: Oliver D
authors.initials: OD
authors.lastname: King
authors.forename: Robin
authors.initials: R
authors.lastname: Reed
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Crabtree
authors.forename: Ian P
authors.initials: IP
authors.lastname: Blair
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Glass
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004268:DNA-Binding Proteins / Q000235:genetics*; D003712:Dendrites / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D059472:Exome / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D009046:Motor Neurons / Q000166:cytology / Q000502:physiology; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D034702:RNA-Binding Protein FUS / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics*; D055815:Young Adult
chemical_list: C501959:BANF1 protein, human; D004268:DNA-Binding Proteins; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D009687:Nuclear Proteins; D034702:RNA-Binding Protein FUS; C502810:SS18L1 protein, human; D015534:Trans-Activators