title: Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease.
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.
authors.affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
authors.forename: Cyril
authors.initials: C
authors.lastname: Pottier
authors.forename: Kevin F
authors.initials: KF
authors.lastname: Bieniek
authors.forename: NiCole
authors.initials: N
authors.lastname: Finch
authors.forename: Maartje
authors.initials: M
authors.lastname: van de Vorst
authors.forename: Matt
authors.initials: M
authors.lastname: Baker
authors.forename: Ralph
authors.initials: R
authors.lastname: Perkersen
authors.forename: Patricia
authors.initials: P
authors.lastname: Brown
authors.forename: Thomas
authors.initials: T
authors.lastname: Ravenscroft
authors.forename: Marka
authors.initials: M
authors.lastname: van Blitterswijk
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Nicholson
authors.forename: Michael
authors.initials: M
authors.lastname: DeTure
authors.forename: David S
authors.initials: DS
authors.lastname: Knopman
authors.forename: Keith A
authors.initials: KA
authors.lastname: Josephs
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Boylan
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Murray
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D026901:Membrane Transport Proteins; D016472:Motor Neuron Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017422:Sequence Analysis, DNA; D035582:Transcription Factor TFIIIA / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D026901:Membrane Transport Proteins; C409460:OPTN protein, human; D012333:RNA, Messenger; D035582:Transcription Factor TFIIIA; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human