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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adult
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Amyotrophic Lateral Sclerosis / genetics*
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Animals
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Cells, Cultured
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Cerebral Cortex / cytology
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DNA-Binding Proteins / genetics*
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Dendrites / genetics
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Dendrites / metabolism
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Embryo, Mammalian
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Exome / genetics*
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Family Health
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Female
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Genetic Predisposition to Disease / genetics*
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Genotype
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Humans
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Male
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Mice
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Microtubule-Associated Proteins / metabolism
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Middle Aged
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Motor Neurons / cytology
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Motor Neurons / physiology
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Mutation / genetics*
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Nuclear Proteins / genetics*
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RNA-Binding Protein FUS / genetics
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Trans-Activators / genetics*
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Young Adult
Substances
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BANF1 protein, human
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DNA-Binding Proteins
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Microtubule-Associated Proteins
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Mtap2 protein, mouse
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Nuclear Proteins
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RNA-Binding Protein FUS
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SS18L1 protein, human
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Trans-Activators