Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia

Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.

Wieland, Thomas (author)
Richter, Benjamin (author)
Ruf, Wolfgang (author)
Schaeffer, Veronique (author)
Mueller, Kathrin (author)
Marroquin, Nicolai (author)
Nordin, FridaUmeå universitet,Klinisk neurovetenskap(Swepub:umu)franon02 (author)
Huebers, Annemarie (author)
Weydt, Patrick (author)
Pinto, Susana (author)
Press, RayomondKarolinska Institutet (author)
Millecamps, Stephanie (author)
Molko, Nicolas (author)
Bernard, Emilien (author)
Desnuelle, Claude (author)
Soriani, Marie-Helene (author)
Dorst, Johannes (author)
Graf, Elisabeth (author)
Nordström, UlrikaUmeå universitet,Klinisk neurovetenskap(Swepub:umu)ulno0003 (author)
Feiler, Marisa S. (author)
Putz, Stefan (author)
Boeckers, Tobias M. (author)
Meyer, Thomas (author)
Winkler, Andrea S. (author)
Winkelman, Juliane (author)
de Carvalho, Mamede (author)
Thal, Dietmar R. (author)
Otto, Markus (author)
Brännström, ThomasUmeå universitet,Institutionen för medicinsk biovetenskap(Swepub:umu)thbr0001 (author)
Volk, Alexander E. (author)
Kursula, Petri (author)
Danzer, Karin M. (author)
Lichtner, Peter (author)
Dikic, Ivan (author)
Meitinger, Thomas (author)
Ludolph, Albert C. (author)
Strom, Tim M. (author)
Andersen, Peter M.Umeå universitet,Klinisk neurovetenskap(Swepub:umu)pean0001 (author)
Weishaupt, Jochen H. (author)
Umeå universitetKlinisk neurovetenskap (creator_code:org_t)

In:Nature Neuroscience: Springer Science and Business Media LLC18:5, s. 631-+1097-62561546-1726

By the author/editor: Freischmidt, Axe ...; Wieland, Thomas; Richter, Benjami ...; Ruf, Wolfgang; Schaeffer, Veron ...; Mueller, Kathrin; show more...; Marroquin, Nicol ...; Nordin, Frida; Huebers, Annemar ...; Weydt, Patrick; Pinto, Susana; Press, Rayomond; Millecamps, Step ...; Molko, Nicolas; Bernard, Emilien; Desnuelle, Claud ...; Soriani, Marie-H ...; Dorst, Johannes; Graf, Elisabeth; Nordström, Ulrik ...; Feiler, Marisa S ...; Putz, Stefan; Boeckers, Tobias ...; Meyer, Thomas; Winkler, Andrea ...; Winkelman, Julia ...; de Carvalho, Mam ...; Thal, Dietmar R.; Otto, Markus; Brännström, Thom ...; Volk, Alexander ...; Kursula, Petri; Danzer, Karin M.; Lichtner, Peter; Dikic, Ivan; Meitinger, Thoma ...; Ludolph, Albert ...; Strom, Tim M.; Andersen, Peter ...; Weishaupt, Joche ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

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