Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways.

Cirulli, Elizabeth T.; Lasseigne, Brittany N; Petrovski, Slave; Sapp, Peter C; Dion, Patrick A.; Leblond, Claire S.; Couthouis, Julien; Lu, Yi-Fan; Wang, Quanli; Krueger, Brian J.; Ren, Zhong-fa; Keebler, Jonathan E. M.; Han, Yujun; Levy, Shawn E.; Boone, Braden E.; Wimbish, Jack R.; Waite, Lindsay L.; Jones, Angela L.; Carulli, John P.; Day-Williams, Aaron G; Staropoli, John F.; Xin, Winnie W; Chesi, Alessandra; Raphael, Alya R.; McKenna-Yasek, Diane; Cady, Janet; Vianney de Jong, J M B; Kenna, Kevin P; Smith, Bradley N.; Topp, Simon; Miller, Jack; Gkazi, Athina-Soragia; Al-Chalabi, Ammar; van den Berg, Leonard H.; Veldink, Jan Herman; Silani, Vincenzo; Ticozzi, Nicola; Shaw, Christopher E.; Baloh, Robert H; Appel, Stanley H; Simpson, Ericka; Lagier-Tourenne, Clotilde; Pulst, Stefan M.; Gibson, Summer B; Trojanowski, John Q.; Elman, Lauren; McCluskey, Leo; Grossman, Murray; Shneider, Neil A; Chung, Wendy K; Ravits, John M; Glass, Jonathan D.; Sims, Katherine B; Van Deerlin, Vivianna M.; Maniatis, Tom; Hayes, Sebastian D.; Ordureau, Alban; Swarup, Sharan; Landers, John; Baas, Frank; Allen, Andrew S; Bedlack, Richard S.; Harper, J Wade; Gitler, Aaron D.; Rouleau, Guy A.; Brown, Robert; Harms, Matthew B; Cooper, Gregory M.; Harris, Tim; Myers, Richard M.; Goldstein, David B

doi:10.1126/science.aaa3650

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Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways.

Author(s): Elizabeth T. Cirulli, Brittany N Lasseigne, Slave Petrovski, Peter Sapp, Patrick Dion, Claire Leblond, Julien Couthouis, Yi-Fan Lu, Quanli Wang, Brian Krueger, Zhong-fa Ren, Jonathan E. M. Keebler, Yujun Han, Shawn E. Levy, Braden Boone, Jack Wimbish, Lindsay Waite, Angela Jones, John Carulli, Aaron G Day-Williams, John Staropoli, Winnie W Xin, Alessandra Chesi, Alya Raphael, Diane McKenna-Yasek, Janet Cady, J M B Vianney de Jong, Kevin Kenna, Bradley N. Smith, Simon Topp, Jack Miller, Athina-Soragia Gkazi, Ammar Al-Chalabi, Leonard van den Berg, Jan Veldink, Vincenzo Silani, Nicola Ticozzi, Christopher E. Shaw, Robert H Baloh, Stanley H Appel, Ericka Simpson, Clotilde Lagier-Tourenne, Stefan Pulst, Summer Gibson, John Trojanowski, Lauren Elman, Leo McCluskey, Murray Grossman, Neil Shneider, Wendy Chung, John M Ravits, Jonathan Glass, Katherine B Sims, Vivianna M. Van Deerlin, Tom Maniatis, Sebastian D. Hayes, Alban Ordureau, Sharan Swarup, John Landers, Frank Baas, Andrew S Allen, Richard S. Bedlack, J Harper, Aaron Gitler, Guy Rouleau, Robert Brown, Matthew B Harms, Gregory M. Cooper, Tim Harris, Richard M. Myers, David B Goldstein

Publication date: 2015-03-27

Journal: Science (New York, N.Y.)

Publisher: American Association for the Advancement of Science (AAAS)

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Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.