Exome sequencing to identify de novo mutations in sporadic ALS trios

Alessandra Chesi; Brett T. Staahl; Ana Jovičić; Julien Couthouis; Maria Fasolino; Alya R. Raphael; Tomohiro Yamazaki; Laura Elias; Meraida Polak; Crystal Kelly; Kelly L. Williams; Jennifer A. Fifita; Nicholas J. Maragakis; Garth A. Nicholson; Oliver D. King; Robin Reed; Gerald R. Crabtree; Ian P. Blair; Jonathan D. Glass; Aaron D. Gitler

doi:10.1038/nn.3412

Exome sequencing to identify de novo mutations in sporadic ALS trios

Alessandra Chesi^*, Brett T. Staahl, Ana Jovičić, Julien Couthouis, Maria Fasolino, Alya R. Raphael, Tomohiro Yamazaki, Laura Elias, Meraida Polak, Crystal Kelly, Kelly L. Williams, Jennifer A. Fifita, Nicholas J. Maragakis, Garth A. Nicholson, Oliver D. King, Robin Reed, Gerald R. Crabtree, Ian P. Blair, Jonathan D. Glass, Aaron D. Gitler

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

118 Citations (Scopus)

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.

Original language	English
Pages (from-to)	851-855
Number of pages	5
Journal	Nature Neuroscience
Volume	16
Issue number	7
DOIs	https://doi.org/10.1038/nn.3412
Publication status	Published - 2013

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Chesi, A., Staahl, B. T., Jovičić, A., Couthouis, J., Fasolino, M., Raphael, A. R., Yamazaki, T., Elias, L., Polak, M., Kelly, C., Williams, K. L., Fifita, J. A., Maragakis, N. J., Nicholson, G. A., King, O. D., Reed, R., Crabtree, G. R., Blair, I. P., Glass, J. D., & Gitler, A. D. (2013). Exome sequencing to identify de novo mutations in sporadic ALS trios. Nature Neuroscience, 16(7), 851-855. https://doi.org/10.1038/nn.3412

@article{c6ad13828cff461e86b4130e686fdc34,

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.",

author = "Alessandra Chesi and Staahl, {Brett T.} and Ana Jovi{\v c}i{\'c} and Julien Couthouis and Maria Fasolino and Raphael, {Alya R.} and Tomohiro Yamazaki and Laura Elias and Meraida Polak and Crystal Kelly and Williams, {Kelly L.} and Fifita, {Jennifer A.} and Maragakis, {Nicholas J.} and Nicholson, {Garth A.} and King, {Oliver D.} and Robin Reed and Crabtree, {Gerald R.} and Blair, {Ian P.} and Glass, {Jonathan D.} and Gitler, {Aaron D.}",

year = "2013",

doi = "10.1038/nn.3412",

language = "English",

volume = "16",

pages = "851--855",

journal = "Nature Neuroscience",

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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 2013, 'Exome sequencing to identify de novo mutations in sporadic ALS trios', Nature Neuroscience, vol. 16, no. 7, pp. 851-855. https://doi.org/10.1038/nn.3412

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AU - Chesi, Alessandra

AU - Staahl, Brett T.

AU - Jovičić, Ana

AU - Couthouis, Julien

AU - Fasolino, Maria

AU - Raphael, Alya R.

AU - Yamazaki, Tomohiro

AU - Elias, Laura

AU - Polak, Meraida

AU - Kelly, Crystal

AU - Williams, Kelly L.

AU - Fifita, Jennifer A.

AU - Maragakis, Nicholas J.

AU - Nicholson, Garth A.

AU - King, Oliver D.

AU - Reed, Robin

AU - Crabtree, Gerald R.

AU - Blair, Ian P.

AU - Glass, Jonathan D.

AU - Gitler, Aaron D.

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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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VL - 16

SP - 851

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JO - Nature Neuroscience

JF - Nature Neuroscience

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Exome sequencing to identify de novo mutations in sporadic ALS trios

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