Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                
Skip to main content

Advertisement

Springer Nature Link
Log in

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

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Al-Sarraj S, King A, Troakes C, Smith B, Maekawa S, Bodi I, Rogelj B, Al-Chalabi A, Hortobagyi T, Shaw CE (2011) p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol 122:691–702. doi:10.1007/s00401-011-0911-2

    Article  CAS  PubMed  Google Scholar 

  2. Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611. doi:10.1016/j.bbrc.2006.10.093

    Article  CAS  PubMed  Google Scholar 

  3. Arai T, Nonaka T, Hasegawa M, Akiyama H, Yoshida M, Hashizume Y, Tsuchiya K, Oda T, Ikeda K (2003) Neuronal and glial inclusions in frontotemporal dementia with or without motor neuron disease are immunopositive for p62. Neurosci Lett 342:41–44

    Article  CAS  PubMed  Google Scholar 

  4. Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442:916–919. doi:10.1038/nature05016

    Article  CAS  PubMed  Google Scholar 

  5. Belzil VV, Daoud H, Desjarlais A, Bouchard JP, Dupre N, Camu W, Dion PA, Rouleau GA (2011) Analysis of OPTN as a causative gene for amyotrophic lateral sclerosis. Neurobiol Aging 32(555):e513–e554. doi:10.1016/j.neurobiolaging.2010.10.001

    Google Scholar 

  6. Bennion Callister J, Pickering-Brown SM (2014) Pathogenesis/genetics of frontotemporal dementia and how it relates to ALS. Exp Neurol 262(Pt B):84–90. doi:10.1016/j.expneurol.2014.06.001

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Boomsma DI, Wijmenga C, Slagboom EP, Swertz MA, Karssen LC, Abdellaoui A, Ye K, Guryev V, Vermaat M, van Dijk F, Francioli LC, Hottenga JJ, Laros JF, Li Q, Li Y, Cao H, Chen R, Du Y, Li N, Cao S, van Setten J, Menelaou A, Pulit SL, Hehir-Kwa JY, Beekman M, Elbers CC, Byelas H, de Craen AJ, Deelen P, Dijkstra M, den Dunnen JT, de Knijff P, Houwing-Duistermaat J, Koval V, Estrada K, Hofman A, Kanterakis A, Enckevort D, Mai H, Kattenberg M, van Leeuwen EM, Neerincx PB, Oostra B, Rivadeneira F, Suchiman EH, Uitterlinden AG, Willemsen G, Wolffenbuttel BH, Wang J, de Bakker PI, van Ommen GJ, van Duijn CM (2014) The Genome of the Netherlands: design, and project goals. Eur J Hum Genet 22:221–227. doi:10.1038/ejhg.2013.118

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Cady J, Allred P, Bali T, Pestronk A, Goate A, Miller TM, Mitra RD, Ravits J, Harms MB, Baloh RH (2015) Amyotrophic lateral sclerosis onset is influenced by the burden of rare variants in known amyotrophic lateral sclerosis genes. Ann Neurol 77:100–113. doi:10.1002/ana.24306

    Article  CAS  PubMed  Google Scholar 

  9. Chio A, Calvo A, Mazzini L, Cantello R, Mora G, Moglia C, Corrado L, D’Alfonso S, Majounie E, Renton A, Pisano F, Ossola I, Brunetti M, Traynor BJ, Restagno G (2012) Extensive genetics of ALS: a population-based study in Italy. Neurology 79:1983–1989. doi:10.1212/WNL.0b013e3182735d36

    Article  PubMed Central  PubMed  Google Scholar 

  10. Chio A, Restagno G, Brunetti M, Ossola I, Calvo A, Canosa A, Moglia C, Floris G, Tacconi P, Marrosu F, Marrosu MG, Murru MR, Majounie E, Renton AE, Abramzon Y, Pugliatti M, Sotgiu MA, Traynor BJ, Borghero G (2012) ALS/FTD phenotype in two Sardinian families carrying both C9ORF72 and TARDBP mutations. J Neurol Neurosurg Psychiatry 83:730–733. doi:10.1136/jnnp-2012-302219

    Article  PubMed  Google Scholar 

  11. Cirulli ET, Lasseigne BN, Petrovski S, Sapp PC, Dion PA, Leblond CS, Couthouis J, Lu YF, Wang Q, Krueger BJ, Ren Z, Keebler J, Han Y, Levy SE, Boone BE, Wimbish JR, Waite LL, Jones AL, Carulli JP, Day-Williams AG, Staropoli JF, Xin WW, Chesi A, Raphael AR, McKenna-Yasek D, Cady J, Vianney de Jong JM, Kenna KP, Smith BN, Topp S, Miller J, Gkazi A, Al-Chalabi A, van den Berg LH, Veldink J, Silani V, Ticozzi N, Shaw CE, Baloh RH, Appel S, Simpson E, Lagier-Tourenne C, Pulst SM, Gibson S, Trojanowski JQ, Elman L, McCluskey L, Grossman M, Shneider NA, Chung WK, Ravits JM, Glass JD, Sims KB, Van Deerlin VM, Maniatis T, Hayes SD, Ordureau A, Swarup S, Landers J, Baas F, Allen AS, Bedlack RS, Harper JW, Gitler AD, Rouleau GA, Brown R, Harms MB, Cooper GM, Harris T, Myers RM, Goldstein DB (2015) Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347:1436–1441. doi:10.1126/science.aaa3650

    Article  CAS  PubMed  Google Scholar 

  12. Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, Rademakers R, Vandenberghe R, Dermaut B, Martin JJ, van Duijn C, Peeters K, Sciot R, Santens P, De Pooter T, Mattheijssens M, Van den Broeck M, Cuijt I, Vennekens K, De Deyn PP, Kumar-Singh S, Van Broeckhoven C (2006) Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442:920–924. doi:10.1038/nature05017

    Article  CAS  PubMed  Google Scholar 

  13. Czell D, Andersen PM, Morita M, Neuwirth C, Perren F, Weber M (2013) Phenotypes in Swiss patients with familial ALS carrying TARDBP mutations. Neurodegener Dis 12:150–155. doi:10.1159/000345835

    Article  CAS  PubMed  Google Scholar 

  14. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, Kouri N, Wojtas A, Sengdy P, Hsiung GY, Karydas A, Seeley WW, Josephs KA, Coppola G, Geschwind DH, Wszolek ZK, Feldman H, Knopman DS, Petersen RC, Miller BL, Dickson DW, Boylan KB, Graff-Radford NR, Rademakers R (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256. doi:10.1016/j.neuron.2011.09.011

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Del Bo R, Tiloca C, Pensato V, Corrado L, Ratti A, Ticozzi N, Corti S, Castellotti B, Mazzini L, Soraru G, Cereda C, D’Alfonso S, Gellera C, Comi GP, Silani V (2011) Novel optineurin mutations in patients with familial and sporadic amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 82:1239–1243. doi:10.1136/jnnp.2011.242313

    Article  PubMed  Google Scholar 

  16. Drmanac R, Sparks AB, Callow MJ, Halpern AL, Burns NL, Kermani BG, Carnevali P, Nazarenko I, Nilsen GB, Yeung G, Dahl F, Fernandez A, Staker B, Pant KP, Baccash J, Borcherding AP, Brownley A, Cedeno R, Chen L, Chernikoff D, Cheung A, Chirita R, Curson B, Ebert JC, Hacker CR, Hartlage R, Hauser B, Huang S, Jiang Y, Karpinchyk V, Koenig M, Kong C, Landers T, Le C, Liu J, McBride CE, Morenzoni M, Morey RE, Mutch K, Perazich H, Perry K, Peters BA, Peterson J, Pethiyagoda CL, Pothuraju K, Richter C, Rosenbaum AM, Roy S, Shafto J, Sharanhovich U, Shannon KW, Sheppy CG, Sun M, Thakuria JV, Tran A, Vu D, Zaranek AW, Wu X, Drmanac S, Oliphant AR, Banyai WC, Martin B, Ballinger DG, Church GM, Reid CA (2010) Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays. Science 327:78–81. doi:10.1126/science.1181498

    Article  CAS  PubMed  Google Scholar 

  17. Fingert JH, Robin AL, Stone JL, Roos BR, Davis LK, Scheetz TE, Bennett SR, Wassink TH, Kwon YH, Alward WL, Mullins RF, Sheffield VC, Stone EM (2011) Copy number variations on chromosome 12q14 in patients with normal tension glaucoma. Hum Mol Genet 20:2482–2494. doi:10.1093/hmg/ddr123

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Freischmidt A, Wieland T, Richter B, Ruf W, Schaeffer V, Muller K, Marroquin N, Nordin F, Hubers A, Weydt P, Pinto S, Press R, Millecamps S, Molko N, Bernard E, Desnuelle C, Soriani MH, Dorst J, Graf E, Nordstrom U, Feiler MS, Putz S, Boeckers TM, Meyer T, Winkler AS, Winkelman J, de Carvalho M, Thal DR, Otto M, Brannstrom T, Volk AE, Kursula P, Danzer KM, Lichtner P, Dikic I, Meitinger T, Ludolph AC, Strom TM, Andersen PM, Weishaupt JH (2015) Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci. doi:10.1038/nn.4000

    PubMed  Google Scholar 

  19. Galluzzi L, Kepp O, Kroemer G (2011) Autophagy and innate immunity ally against bacterial invasion. EMBO J 30:3213–3214. doi:10.1038/emboj.2011.244

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Gilissen C, Hehir-Kwa JY, Thung DT, van de Vorst M, van Bon BW, Willemsen MH, Kwint M, Janssen IM, Hoischen A, Schenck A, Leach R, Klein R, Tearle R, Bo T, Pfundt R, Yntema HG, de Vries BB, Kleefstra T, Brunner HG, Vissers LE, Veltman JA (2014) Genome sequencing identifies major causes of severe intellectual disability. Nature 511:344–347. doi:10.1038/nature13394

    Article  CAS  PubMed  Google Scholar 

  21. Gleason CE, Ordureau A, Gourlay R, Arthur JS, Cohen P (2011) Polyubiquitin binding to optineurin is required for optimal activation of TANK-binding kinase 1 and production of interferon beta. J Biol Chem 286:35663–35674. doi:10.1074/jbc.M111.267567

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Graff-Radford NR, Woodruff BK (2007) Frontotemporal dementia. Semin Neurol 27:48–57. doi:10.1055/s-2006-956755

    Article  PubMed  Google Scholar 

  23. Hardy J, Rogaeva E (2014) Motor neuron disease and frontotemporal dementia: sometimes related, sometimes not. Exp Neurol 262(Pt B):75–83. doi:10.1016/j.expneurol.2013.11.006

    Article  CAS  PubMed  Google Scholar 

  24. Hiscott J (2007) Convergence of the NF-kappaB and IRF pathways in the regulation of the innate antiviral response. Cytokine Growth Factor Rev 18:483–490. doi:10.1016/j.cytogfr.2007.06.002

    Article  CAS  PubMed  Google Scholar 

  25. Huey ED, Ferrari R, Moreno JH, Jensen C, Morris CM, Potocnik F, Kalaria RN, Tierney M, Wassermann EM, Hardy J, Grafman J, Momeni P (2012) FUS and TDP43 genetic variability in FTD and CBS. Neurobiol Aging 33:1016.e9–1016.e17. doi:10.1016/j.neurobiolaging.2011.08.004

    Article  CAS  Google Scholar 

  26. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P (1998) Association of missense and 5’-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705. doi:10.1038/31508

    Article  CAS  PubMed  Google Scholar 

  27. Ingram EM, Spillantini MG (2002) Tau gene mutations: dissecting the pathogenesis of FTDP-17. Trends Mol Med 8:555–562

    Article  CAS  PubMed  Google Scholar 

  28. Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208. doi:10.1126/science.1166066

    Article  CAS  PubMed  Google Scholar 

  29. Leverenz JB, Yu CE, Montine TJ, Steinbart E, Bekris LM, Zabetian C, Kwong LK, Lee VM, Schellenberg GD, Bird TD (2007) A novel progranulin mutation associated with variable clinical presentation and tau, TDP43 and alpha-synuclein pathology. Brain 130:1360–1374. doi:10.1093/brain/awm069

    Article  CAS  PubMed  Google Scholar 

  30. Liu EY, Russ J, Wu K, Neal D, Suh E, McNally AG, Irwin DJ, Van Deerlin VM, Lee EB (2014) C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD. Acta Neuropathol 128:525–541. doi:10.1007/s00401-014-1286-y

    Article  CAS  PubMed  Google Scholar 

  31. Lomen-Hoerth C, Anderson T, Miller B (2002) The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 59:1077–1079

    Article  PubMed  Google Scholar 

  32. Luigetti M, Lattante S, Zollino M, Conte A, Marangi G, Del Grande A, Sabatelli M (2011) SOD1 G93D sporadic amyotrophic lateral sclerosis (SALS) patient with rapid progression and concomitant novel ANG variant. Neurobiol Aging 32(1924):e1915–e1928. doi:10.1016/j.neurobiolaging.2011.04.004

    Google Scholar 

  33. Mackenzie IR, Baborie A, Pickering-Brown S, Du Plessis D, Jaros E, Perry RH, Neary D, Snowden JS, Mann DM (2006) Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype. Acta Neuropathol 112:539–549. doi:10.1007/s00401-006-0138-9

    Article  PubMed Central  PubMed  Google Scholar 

  34. Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, Chio A, Restagno G, Nicolaou N, Simon-Sanchez J, van Swieten JC, Abramzon Y, Johnson JO, Sendtner M, Pamphlett R, Orrell RW, Mead S, Sidle KC, Houlden H, Rohrer JD, Morrison KE, Pall H, Talbot K, Ansorge O, Hernandez DG, Arepalli S, Sabatelli M, Mora G, Corbo M, Giannini F, Calvo A, Englund E, Borghero G, Floris GL, Remes AM, Laaksovirta H, McCluskey L, Trojanowski JQ, Van Deerlin VM, Schellenberg GD, Nalls MA, Drory VE, Lu CS, Yeh TH, Ishiura H, Takahashi Y, Tsuji S, Le Ber I, Brice A, Drepper C, Williams N, Kirby J, Shaw P, Hardy J, Tienari PJ, Heutink P, Morris HR, Pickering-Brown S, Traynor BJ (2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 11:323–330. doi:10.1016/S1474-4422(12)70043-1

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H (2010) Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465:223–226. doi:10.1038/nature08971

    Article  CAS  PubMed  Google Scholar 

  36. McMillan CT, Russ J, Wood EM, Irwin DJ, Grossman M, McCluskey L, Elman L, Van Deerlin V, Lee EB (2015) C9orf72 promoter hypermethylation is neuroprotective: neuroimaging and neuropathologic evidence. Neurology. doi:10.1212/WNL.0000000000001495

    Google Scholar 

  37. Michaelson JJ, Shi Y, Gujral M, Zheng H, Malhotra D, Jin X, Jian M, Liu G, Greer D, Bhandari A, Wu W, Corominas R, Peoples A, Koren A, Gore A, Kang S, Lin GN, Estabillo J, Gadomski T, Singh B, Zhang K, Akshoomoff N, Corsello C, McCarroll S, Iakoucheva LM, Li Y, Wang J, Sebat J (2012) Whole-genome sequencing in autism identifies hot spots for de novo germline mutation. Cell 151:1431–1442. doi:10.1016/j.cell.2012.11.019

  38. Millecamps S, Boillee S, Chabrol E, Camu W, Cazeneuve C, Salachas F, Pradat PF, Danel-Brunaud V, Vandenberghe N, Corcia P, Le Forestier N, Lacomblez L, Bruneteau G, Seilhean D, Brice A, Feingold J, Meininger V, LeGuern E (2011) Screening of OPTN in French familial amyotrophic lateral sclerosis. Neurobiol Aging 32(557):e511–e553. doi:10.1016/j.neurobiolaging.2010.11.005

    Google Scholar 

  39. Morton S, Hesson L, Peggie M, Cohen P (2008) Enhanced binding of TBK1 by an optineurin mutant that causes a familial form of primary open angle glaucoma. FEBS Lett 582:997–1002. doi:10.1016/j.febslet.2008.02.047

    Article  CAS  PubMed  Google Scholar 

  40. Mukherjee O, Pastor P, Cairns NJ, Chakraverty S, Kauwe JS, Shears S, Behrens MI, Budde J, Hinrichs AL, Norton J, Levitch D, Taylor-Reinwald L, Gitcho M, Tu PH, Tenenholz Grinberg L, Liscic RM, Armendariz J, Morris JC, Goate AM (2006) HDDD2 is a familial frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions caused by a missense mutation in the signal peptide of progranulin. Ann Neurol 60:314–322. doi:10.1002/ana.20963

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IR (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–2931. doi:10.1093/brain/awp214

    Article  PubMed Central  PubMed  Google Scholar 

  42. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133. doi:10.1126/science.1134108

    Article  CAS  PubMed  Google Scholar 

  43. Rademakers R, Baker M, Nicholson AM, Rutherford NJ, Finch N, Soto-Ortolaza A, Lash J, Wider C, Wojtas A, DeJesus-Hernandez M, Adamson J, Kouri N, Sundal C, Shuster EA, Aasly J, MacKenzie J, Roeber S, Kretzschmar HA, Boeve BF, Knopman DS, Petersen RC, Cairns NJ, Ghetti B, Spina S, Garbern J, Tselis AC, Uitti R, Das P, Van Gerpen JA, Meschia JF, Levy S, Broderick DF, Graff-Radford N, Ross OA, Miller BB, Swerdlow RH, Dickson DW, Wszolek ZK (2012) Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet 44:200–205. doi:10.1038/ng.1027

    Article  CAS  Google Scholar 

  44. Rademakers R, Neumann M, Mackenzie IR (2012) Advances in understanding the molecular basis of frontotemporal dementia. Nat Rev Neurol 8:423–434. doi:10.1038/nrneurol.2012.117

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, Kalimo H, Paetau A, Abramzon Y, Remes AM, Kaganovich A, Scholz SW, Duckworth J, Ding J, Harmer DW, Hernandez DG, Johnson JO, Mok K, Ryten M, Trabzuni D, Guerreiro RJ, Orrell RW, Neal J, Murray A, Pearson J, Jansen IE, Sondervan D, Seelaar H, Blake D, Young K, Halliwell N, Callister JB, Toulson G, Richardson A, Gerhard A, Snowden J, Mann D, Neary D, Nalls MA, Peuralinna T, Jansson L, Isoviita VM, Kaivorinne AL, Holtta-Vuori M, Ikonen E, Sulkava R, Benatar M, Wuu J, Chio A, Restagno G, Borghero G, Sabatelli M, Heckerman D, Rogaeva E, Zinman L, Rothstein JD, Sendtner M, Drepper C, Eichler EE, Alkan C, Abdullaev Z, Pack SD, Dutra A, Pak E, Hardy J, Singleton A, Williams NM, Heutink P, Pickering-Brown S, Morris HR, Tienari PJ, Traynor BJ (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268. doi:10.1016/j.neuron.2011.09.010

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Russ J, Liu EY, Wu K, Neal D, Suh E, Irwin DJ, McMillan CT, Harms MB, Cairns NJ, Wood EM, Xie SX, Elman L, McCluskey L, Grossman M, Van Deerlin VM, Lee EB (2015) Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier. Acta Neuropathol 129:39–52. doi:10.1007/s00401-014-1365-0

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Sampathu DM, Neumann M, Kwong LK, Chou TT, Micsenyi M, Truax A, Bruce J, Grossman M, Trojanowski JQ, Lee VM (2006) Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies. Am J Pathol 169:1343–1352. doi:10.2353/ajpath.2006.060438

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Schneider CA, Rasband WS, Eliceiri KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9:671–675

    Article  CAS  PubMed  Google Scholar 

  49. Sieben A, Van Langenhove T, Engelborghs S, Martin JJ, Boon P, Cras P, De Deyn PP, Santens P, Van Broeckhoven C, Cruts M (2012) The genetics and neuropathology of frontotemporal lobar degeneration. Acta Neuropathol 124:353–372. doi:10.1007/s00401-012-1029-x

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Solski JA, Williams KL, Yang S, Nicholson GA, Blair IP (2012) Mutation analysis of the optineurin gene in familial amyotrophic lateral sclerosis. Neurobiol Aging 33:210.e9–210.e10. doi:10.1016/j.neurobiolaging.2011.09.023

    Article  CAS  Google Scholar 

  51. Tu D, Zhu Z, Zhou AY, Yun CH, Lee KE, Toms AV, Li Y, Dunn GP, Chan E, Thai T, Yang S, Ficarro SB, Marto JA, Jeon H, Hahn WC, Barbie DA, Eck MJ (2013) Structure and ubiquitination-dependent activation of TANK-binding kinase 1. Cell Rep 3:747–758. doi:10.1016/j.celrep.2013.01.033

    Article  CAS  PubMed  Google Scholar 

  52. Tumer Z, Bertelsen B, Gredal O, Magyari M, Nielsen KC, Lucamp Gronskov K, Brondum-Nielsen K (2012) Novel heterozygous nonsense mutation of the OPTN gene segregating in a Danish family with ALS. Neurobiol Aging 33(208):e201–e205. doi:10.1016/j.neurobiolaging.2011.07.001

    Google Scholar 

  53. van Blitterswijk M, Baker MC, Bieniek KF, Knopman DS, Josephs KA, Boeve B, Caselli R, Wszolek ZK, Petersen R, Graff-Radford NR, Boylan KB, Dickson DW, Rademakers R (2013) Profilin-1 mutations are rare in patients with amyotrophic lateral sclerosis and frontotemporal dementia. Amyotroph Lateral Scler Frontotemporal Degener 14:463–469. doi:10.3109/21678421.2013.787630

    Article  PubMed Central  PubMed  Google Scholar 

  54. van Blitterswijk M, Baker MC, DeJesus-Hernandez M, Ghidoni R, Benussi L, Finger E, Hsiung GY, Kelley BJ, Murray ME, Rutherford NJ, Brown PE, Ravenscroft T, Mullen B, Ash PE, Bieniek KF, Hatanpaa KJ, Karydas A, Wood EM, Coppola G, Bigio EH, Lippa C, Strong MJ, Beach TG, Knopman DS, Huey ED, Mesulam M, Bird T, White CL 3rd, Kertesz A, Geschwind DH, Van Deerlin VM, Petersen RC, Binetti G, Miller BL, Petrucelli L, Wszolek ZK, Boylan KB, Graff-Radford NR, Mackenzie IR, Boeve BF, Dickson DW, Rademakers R (2013) C9ORF72 repeat expansions in cases with previously identified pathogenic mutations. Neurology 81:1332–1341. doi:10.1212/WNL.0b013e3182a8250c

    Article  PubMed Central  PubMed  Google Scholar 

  55. van Blitterswijk M, DeJesus-Hernandez M, Rademakers R (2012) How do C9ORF72 repeat expansions cause amyotrophic lateral sclerosis and frontotemporal dementia: can we learn from other noncoding repeat expansion disorders? Curr Opin Neurol 25:689–700. doi:10.1097/WCO.0b013e32835a3efb

    Article  PubMed Central  PubMed  Google Scholar 

  56. van Blitterswijk M, van Es MA, Hennekam EA, Dooijes D, van Rheenen W, Medic J, Bourque PR, Schelhaas HJ, van der Kooi AJ, de Visser M, de Bakker PI, Veldink JH, van den Berg LH (2012) Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Hum Mol Genet 21:3776–3784. doi:10.1093/hmg/dds199

    Article  PubMed  Google Scholar 

  57. Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211. doi:10.1126/science.1165942

    Article  CAS  PubMed  Google Scholar 

  58. Weishaupt JH, Waibel S, Birve A, Volk AE, Mayer B, Meyer T, Ludolph AC, Andersen PM (2013) A novel optineurin truncating mutation and three glaucoma-associated missense variants in patients with familial amyotrophic lateral sclerosis in Germany. Neurobiol Aging 34:1516.e9–1516.e15. doi:10.1016/j.neurobiolaging.2012.09.007

    Article  CAS  Google Scholar 

  59. Wild P, Farhan H, McEwan DG, Wagner S, Rogov VV, Brady NR, Richter B, Korac J, Waidmann O, Choudhary C, Dotsch V, Bumann D, Dikic I (2011) Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333:228–233. doi:10.1126/science.1205405

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Wong YC, Holzbaur EL (2014) Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc Natl Acad Sci 111:E4439–E4448. doi:10.1073/pnas.1405752111

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Wu CH, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K, Lowe P, Koppers M, McKenna-Yasek D, Baron DM, Kost JE, Gonzalez-Perez P, Fox AD, Adams J, Taroni F, Tiloca C, Leclerc AL, Chafe SC, Mangroo D, Moore MJ, Zitzewitz JA, Xu ZS, van den Berg LH, Glass JD, Siciliano G, Cirulli ET, Goldstein DB, Salachas F, Meininger V, Rossoll W, Ratti A, Gellera C, Bosco DA, Bassell GJ, Silani V, Drory VE, Brown RH Jr, Landers JE (2012) Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488:499–503. doi:10.1038/nature11280

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Cyril Pottier, Kevin F. Bieniek, NiCole Finch, Matt Baker, Ralph Perkersen, Patricia Brown, Thomas Ravenscroft, Marka van Blitterswijk, Alexandra M. Nicholson, Michael DeTure, Melissa E. Murray, Dennis W. Dickson & Rosa Rademakers

  2. Mayo Graduate School, Mayo Clinic, Rochester, MN, USA

    Kevin F. Bieniek

  3. Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands

    Maartje van de Vorst, Joris A. Veltman & Christian Gilissen

  4. Department of Neurology, Mayo Clinic, Rochester, MN, USA

    David S. Knopman, Keith A. Josephs, Joseph E. Parisi, Ronald C. Petersen & Bradley F. Boeve

  5. Department of Neurology, Mayo Clinic, Jacksonville, FL, USA

    Kevin B. Boylan & Neill R. Graff-Radford

  6. Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands

    Joris A. Veltman

Authors
  1. Cyril Pottier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kevin F. Bieniek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. NiCole Finch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maartje van de Vorst
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matt Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ralph Perkersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Patricia Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Thomas Ravenscroft
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marka van Blitterswijk
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alexandra M. Nicholson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michael DeTure
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. David S. Knopman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Keith A. Josephs
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Joseph E. Parisi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ronald C. Petersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Kevin B. Boylan
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Bradley F. Boeve
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Neill R. Graff-Radford
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Joris A. Veltman
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Christian Gilissen
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Melissa E. Murray
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Dennis W. Dickson
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Rosa Rademakers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rosa Rademakers.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 161 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pottier, C., Bieniek, K.F., Finch, N. et al. Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease. Acta Neuropathol 130, 77–92 (2015). https://doi.org/10.1007/s00401-015-1436-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-015-1436-x

Keywords

Search

Navigation