Exome sequencing to identify de novo mutations in sporadic ALS trios

UMMS Affiliation

Wellstone Center for FSHD; Department of Cell and Developmental Biology



Document Type


Medical Subject Headings

Adult; Amyotrophic Lateral Sclerosis; Animals; Cells, Cultured; Cerebral Cortex; DNA-Binding Proteins; Dendrites; Embryo, Mammalian; Exome; Family Health; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Mice; Microtubule-Associated Proteins; Middle Aged; Motor Neurons; Mutation; Nuclear Proteins; RNA-Binding Protein FUS; Trans-Activators; Young Adult


Cell Biology | Developmental Biology | Molecular Biology | Molecular Genetics | Musculoskeletal Diseases | Nervous System Diseases | Neuroscience and Neurobiology


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.

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Citation: Chesi A, Staahl BT, Jovičić A, Couthouis J, Fasolino M, Raphael AR, Yamazaki T, Elias L, Polak M, Kelly C, Williams KL, Fifita JA, Maragakis NJ, Nicholson GA, King OD, Reed R, Crabtree GR, Blair IP, Glass JD, Gitler AD. Exome sequencing to identify de novo mutations in sporadic ALS trios. Nat Neurosci. 2013 Jul;16(7):851-5. doi: 10.1038/nn.3412. Link to article on publisher's site

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