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01-07-2015 | Original Paper

Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease

Authors: Cyril Pottier, Kevin F. Bieniek, NiCole Finch, Maartje van de Vorst, Matt Baker, Ralph Perkersen, Patricia Brown, Thomas Ravenscroft, Marka van Blitterswijk, Alexandra M. Nicholson, Michael DeTure, David S. Knopman, Keith A. Josephs, Joseph E. Parisi, Ronald C. Petersen, Kevin B. Boylan, Bradley F. Boeve, Neill R. Graff-Radford, Joris A. Veltman, Christian Gilissen, Melissa E. Murray, Dennis W. Dickson, Rosa Rademakers

Published in: Acta Neuropathologica | Issue 1/2015

Abstract

Frontotemporal lobar degeneration with TAR DNA-binding protein 43 inclusions (FTLD-TDP) is the most common pathology associated with frontotemporal dementia (FTD). Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) and mutations in progranulin (GRN) are the major known genetic causes of FTLD-TDP; however, the genetic etiology in the majority of FTLD-TDP remains unexplained. In this study, we performed whole-genome sequencing in 104 pathologically confirmed FTLD-TDP patients from the Mayo Clinic brain bank negative for C9ORF72 and GRN mutations and report on the contribution of rare single nucleotide and copy number variants in 21 known neurodegenerative disease genes. Interestingly, we identified 5 patients (4.8 %) with variants in optineurin (OPTN) and TANK-binding kinase 1 (TBK1) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the p.Q235* nonsense and p.A481V missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (p.Arg117*) in TBK1. Cases C–E carried heterozygous missense mutations in TBK1, including the p.Glu696Lys mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain. Quantitative mRNA expression and protein analysis in cerebellar tissue showed a striking reduction of OPTN and/or TBK1 expression in 4 out of 5 patients supporting pathogenicity in these specific patients and suggesting a loss-of-function disease mechanism. Importantly, neuropathologic examination showed FTLD-TDP type A in the absence of motor neuron disease in 3 pathogenic mutation carriers. In conclusion, we highlight TBK1 as an important cause of pure FTLD-TDP, identify the first OPTN mutations in FTLD-TDP, and suggest a potential oligogenic basis for at least a subset of FTLD-TDP patients. Our data further add to the growing body of evidence linking ALS and FTD and suggest a key role for the OPTN/TBK1 pathway in these diseases.

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Title: Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease
Authors: Cyril Pottier
Kevin F. Bieniek
NiCole Finch
Maartje van de Vorst
Matt Baker
Ralph Perkersen
Patricia Brown
Thomas Ravenscroft
Marka van Blitterswijk
Alexandra M. Nicholson
Michael DeTure
David S. Knopman
Keith A. Josephs
Joseph E. Parisi
Ronald C. Petersen
Kevin B. Boylan
Bradley F. Boeve
Neill R. Graff-Radford
Joris A. Veltman
Christian Gilissen
Melissa E. Murray
Dennis W. Dickson
Rosa Rademakers
Publication date: 01-07-2015
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 1/2015
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-015-1436-x

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Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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