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Acta Neuropathologica

, Volume 130, Issue 1, pp 77–92 | Cite as

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

  • 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
Original Paper

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.

Keywords

Whole-genome sequencing FTLD-TDP OPTN TBK1 Oligogenic mechanism 

Notes

Acknowledgments

This project was supported by the State of Florida Alzheimer’s Disease Initiative, the Cure PSP brain bank, NIH grants R01 AG037491 (KAJ), R01 NS076471 (RR), R01 NS080882 (RR), R01 AG026251 (RR), P50 AG016574 (RP), UO1 AG006786 (RP). Whole genome sequencing in the Mayo Clinic FTLD-TDP cohort and the Wellderly dataset was performed by Complete Genomics.

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

401_2015_1436_MOESM1_ESM.pdf (161 kb)
Supplementary material 1 (PDF 161 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Cyril Pottier
    • 1
  • Kevin F. Bieniek
    • 1
    • 2
  • NiCole Finch
    • 1
  • Maartje van de Vorst
    • 3
  • Matt Baker
    • 1
  • Ralph Perkersen
    • 1
  • Patricia Brown
    • 1
  • Thomas Ravenscroft
    • 1
  • Marka van Blitterswijk
    • 1
  • Alexandra M. Nicholson
    • 1
  • Michael DeTure
    • 1
  • David S. Knopman
    • 4
  • Keith A. Josephs
    • 4
  • Joseph E. Parisi
    • 4
  • Ronald C. Petersen
    • 4
  • Kevin B. Boylan
    • 5
  • Bradley F. Boeve
    • 4
  • Neill R. Graff-Radford
    • 5
  • Joris A. Veltman
    • 3
    • 6
  • Christian Gilissen
    • 3
  • Melissa E. Murray
    • 1
  • Dennis W. Dickson
    • 1
  • Rosa Rademakers
    • 1
  1. 1.Department of NeuroscienceMayo ClinicJacksonvilleUSA
  2. 2.Mayo Graduate School, Mayo ClinicRochesterUSA
  3. 3.Department of Human GeneticsRadboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical CenterNijmegenThe Netherlands
  4. 4.Department of NeurologyMayo ClinicRochesterUSA
  5. 5.Department of NeurologyMayo ClinicJacksonvilleUSA
  6. 6.Department of Clinical GeneticsMaastricht University Medical CentreMaastrichtThe Netherlands

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