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 C. 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 Anthony Josephs, Joseph E Parisi, Ronald Carl Petersen, Kevin B. Boylan, Bradley F Boeve, Neill R Graff Radford, Joris A. Veltman, Christian GilissenMelissa E Murray, Dennis W Dickson, Rosa V Rademakers

Research output: Contribution to journalArticle

141 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)77-92
Number of pages16
JournalActa Neuropathologica
Volume130
Issue number1
DOIs
StatePublished - May 6 2015

Fingerprint

Frontotemporal Lobar Degeneration
Motor Neuron Disease
DNA-Binding Proteins
Phosphotransferases
Genome
Mutation
Chromosomes, Human, Pair 9
Missense Mutation
Open Reading Frames
Frontotemporal Dementia
Amyotrophic Lateral Sclerosis
Heterozygote
Neurodegenerative Diseases
Virulence
Exons
Nucleotides
Pathology
Messenger RNA

Keywords

  • FTLD-TDP
  • Oligogenic mechanism
  • OPTN
  • TBK1
  • Whole-genome sequencing

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Cite this

Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease. / Pottier, Cyril; Bieniek, Kevin F.; Finch, NiCole C.; van de Vorst, Maartje; Baker, Matt; Perkersen, Ralph; Brown, Patricia; Ravenscroft, Thomas; Van Blitterswijk, Marka; Nicholson, Alexandra M.; Deture, Michael; Knopman, David S; Josephs, Keith Anthony; Parisi, Joseph E; Petersen, Ronald Carl; Boylan, Kevin B.; Boeve, Bradley F; Graff Radford, Neill R; Veltman, Joris A.; Gilissen, Christian; Murray, Melissa E; Dickson, Dennis W; Rademakers, Rosa V.

In: Acta Neuropathologica, Vol. 130, No. 1, 06.05.2015, p. 77-92.

Research output: Contribution to journalArticle

Pottier, Cyril ; Bieniek, Kevin F. ; Finch, NiCole C. ; van de Vorst, Maartje ; Baker, Matt ; Perkersen, Ralph ; Brown, Patricia ; Ravenscroft, Thomas ; Van Blitterswijk, Marka ; Nicholson, Alexandra M. ; Deture, Michael ; Knopman, David S ; Josephs, Keith Anthony ; Parisi, Joseph E ; Petersen, Ronald Carl ; Boylan, Kevin B. ; Boeve, Bradley F ; Graff Radford, Neill R ; Veltman, Joris A. ; Gilissen, Christian ; Murray, Melissa E ; Dickson, Dennis W ; Rademakers, Rosa V. / Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease. In: Acta Neuropathologica. 2015 ; Vol. 130, No. 1. pp. 77-92.
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T1 - Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease

AU - Pottier, Cyril

AU - Bieniek, Kevin F.

AU - Finch, NiCole C.

AU - van de Vorst, Maartje

AU - Baker, Matt

AU - Perkersen, Ralph

AU - Brown, Patricia

AU - Ravenscroft, Thomas

AU - Van Blitterswijk, Marka

AU - Nicholson, Alexandra M.

AU - Deture, Michael

AU - Knopman, David S

AU - Josephs, Keith Anthony

AU - Parisi, Joseph E

AU - Petersen, Ronald Carl

AU - Boylan, Kevin B.

AU - Boeve, Bradley F

AU - Graff Radford, Neill R

AU - Veltman, Joris A.

AU - Gilissen, Christian

AU - Murray, Melissa E

AU - Dickson, Dennis W

AU - Rademakers, Rosa V

PY - 2015/5/6

Y1 - 2015/5/6

N2 - 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.

AB - 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.

KW - FTLD-TDP

KW - Oligogenic mechanism

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KW - TBK1

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