Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia

• Published in: Nature neuroscience Vol. 18; no. 5; pp. 631 - 636
• Main Authors: Freischmidt, Axel, Wieland, Thomas, Richter, Benjamin, Ruf, Wolfgang, Schaeffer, Veronique, Müller, Kathrin, Marroquin, Nicolai, Nordin, Frida, Hübers, Annemarie, Weydt, Patrick, Pinto, Susana, Press, Rayomond, Millecamps, Stéphanie, Molko, Nicolas, Bernard, Emilien, Desnuelle, Claude, Soriani, Marie-Hélène, Dorst, Johannes, Graf, Elisabeth, Nordström, Ulrika, Feiler, Marisa S., Putz, Stefan, Boeckers, Tobias M., Meyer, Thomas, Winkler, Andrea S., Winkelman, Juliane, de Carvalho, Mamede, Thal, Dietmar R., Otto, Markus, Brännström, Thomas, Volk, Alexander E, Kursula, Petri, Danzer, Karin M., Lichtner, Peter, Dikic, Ivan, Meitinger, Thomas, Ludolph, Albert C., Strom, Tim M., Andersen, Peter M., Weishaupt, Jochen H.
• Format: Journal Article
• Language: English
• Published: New York Springer Nature 01.05.2015; Nature Publishing Group US; Nature Publishing Group
• Subjects: 631/208/514/1948; 692/420/2489/144; 692/617/375/132; 692/617/375/365/1917/1285; Alleles; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - epidemiology; Amyotrophic Lateral Sclerosis - genetics; Animal Genetics and Genomics; Behavioral Sciences; Biochemistry, Molecular Biology; Biological Techniques; Biomedicine; Cells, Cultured; Codon, Nonsense; Dementia; Development and progression; DNA Mutational Analysis; Europe - epidemiology; Exome; Female; Frontotemporal Dementia - epidemiology; Frontotemporal Dementia - genetics; Gene Frequency; Genetic aspects; Genetic Heterogeneity; Genetics; Genome-Wide Association Study; Human genetics; Humans; Life Sciences; Male; Medicin och hälsovetenskap; Mutation, Missense; Neurobiology; Neurosciences; Pedigree; Phosphotransferases; Properties; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases - biosynthesis; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - genetics; Sequence Analysis, DNA; Transcription Factor TFIIIA - metabolism; Europe
• ISSN: 1097-6256; 1546-1726; 1546-1726
• DOI: 10.1038/nn.4000

Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 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.