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


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.

SUBMITTER: Cirulli ET 

PROVIDER: S-EPMC4437632 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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

Cirulli Elizabeth T ET   Lasseigne Brittany N BN   Petrovski Slavé S   Sapp Peter C PC   Dion Patrick A PA   Leblond Claire S CS   Couthouis Julien J   Lu Yi-Fan YF   Wang Quanli Q   Krueger Brian J BJ   Ren Zhong Z   Keebler Jonathan J   Han Yujun Y   Levy Shawn E SE   Boone Braden E BE   Wimbish Jack R JR   Waite Lindsay L LL   Jones Angela L AL   Carulli John P JP   Day-Williams Aaron G AG   Staropoli John F JF   Xin Winnie W WW   Chesi Alessandra A   Raphael Alya R AR   McKenna-Yasek Diane D   Cady Janet J   Vianney de Jong J M B JM   Kenna Kevin P KP   Smith Bradley N BN   Topp Simon S   Miller Jack J   Gkazi Athina A   Al-Chalabi Ammar A   van den Berg Leonard H LH   Veldink Jan J   Silani Vincenzo V   Ticozzi Nicola N   Shaw Christopher E CE   Baloh Robert H RH   Appel Stanley S   Simpson Ericka E   Lagier-Tourenne Clotilde C   Pulst Stefan M SM   Gibson Summer S   Trojanowski John Q JQ   Elman Lauren L   McCluskey Leo L   Grossman Murray M   Shneider Neil A NA   Chung Wendy K WK   Ravits John M JM   Glass Jonathan D JD   Sims Katherine B KB   Van Deerlin Vivianna M VM   Maniatis Tom T   Hayes Sebastian D SD   Ordureau Alban A   Swarup Sharan S   Landers John J   Baas Frank F   Allen Andrew S AS   Bedlack Richard S RS   Harper J Wade JW   Gitler Aaron D AD   Rouleau Guy A GA   Brown Robert R   Harms Matthew B MB   Cooper Gregory M GM   Harris Tim T   Myers Richard M RM   Goldstein David B DB  

Science (New York, N.Y.) 20150219 6229


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 phosphoryla  ...[more]

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