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Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis

neurogenetics volume 11, pages 217–225 (2010)Cite this article

Abstract

The finding of TDP-43 as a major component of ubiquitinated protein inclusions in amyotrophic lateral sclerosis (ALS) has led to the identification of 30 mutations in the transactive response-DNA binding protein (TARDBP) gene, encoding TDP-43. All but one are in exon 6, which encodes the glycine-rich domain. The aim of this study was to determine the frequency of TARDBP mutations in a large cohort of motor neurone disease patients from Northern England (42 non-superoxide dismutase 1 (SOD1) familial ALS (FALS), nine ALS-frontotemporal dementia, 474 sporadic ALS (SALS), 45 progressive muscular atrophy cases). We identified four mutations, two of which were novel, in two familial (FALS) and two sporadic (SALS) cases, giving a frequency of TARDBP mutations in non-SOD1 FALS of 5% and SALS of 0.4%. Analysis of clinical data identified that patients had typical ALS, with limb or bulbar onset, and showed considerable variation in age of onset and rapidity of disease course. However, all cases had an absence of clinically overt cognitive dysfunction.

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References

  1. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O'Regan JP, Deng HX et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62

    Article  CAS  PubMed  Google Scholar 

  2. Gros-Louis F, Gaspar C, Rouleau GA (2006) Genetics of familial and sporadic amyotrophic lateral sclerosis. Biochim Biophys Acta 1762:956–972

    CAS  PubMed  Google Scholar 

  3. Kirby J, Heath PR, Shaw PJ, Hamdy FC (2007) Gene expression assays. Adv Clin Chem 44:247–292

    Article  CAS  PubMed  Google Scholar 

  4. Andersen PM (2006) Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene. Curr Neurol Neurosci Rep 6:37–46

    Article  CAS  PubMed  Google Scholar 

  5. Kew JJ, Goldstein LH, Leigh PN, Abrahams S, Cosgrave N, Passingham RE, Frackowiak RS, Brooks DJ (1993) The relationship between abnormalities of cognitive function and cerebral activation in amyotrophic lateral sclerosis. A neuropsychological and positron emission tomography study. Brain 116(Pt 6):1399–1423

    Article  PubMed  Google Scholar 

  6. Neary D, Snowden JS, Mann DM (2000) Cognitive change in motor neurone disease/amyotrophic lateral sclerosis (MND/ALS). J Neurol Sci 180:15–20

    Article  CAS  PubMed  Google Scholar 

  7. Ringholz GM, Appel SH, Bradshaw M, Cooke NA, Mosnik DM, Schulz PE (2005) Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology 65:586–590

    Article  CAS  PubMed  Google Scholar 

  8. Lomen-Hoerth C, Murphy J, Langmore S, Kramer JH, Olney RK, Miller B (2003) Are amyotrophic lateral sclerosis patients cognitively normal? Neurology 60:1094–1097

    CAS  PubMed  Google Scholar 

  9. Morita M, Al-Chalabi A, Andersen PM, Hosler B, Sapp P, Englund E, Mitchell JE, Habgood JJ, de Belleroche J, Xi J et al (2006) A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 66:839–844

    Article  CAS  PubMed  Google Scholar 

  10. Vance C, Al-Chalabi A, Ruddy D, Smith BN, Hu X, Sreedharan J, Siddique T, Schelhaas HJ, Kusters B, Troost D et al (2006) Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2–21.3. Brain 129:868–876

    Article  PubMed  Google Scholar 

  11. Hosler BA, Siddique T, Sapp PC, Sailor W, Huang MC, Hossain A, Daube JR, Nance M, Fan C, Kaplan J et al (2000) Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21–q22. JAMA 284:1664–1669

    Article  CAS  PubMed  Google Scholar 

  12. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133

    Article  CAS  PubMed  Google Scholar 

  13. Ou SH, Wu F, Harrich D, Garcia-Martinez LF, Gaynor RB (1995) Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J Virol 69:3584–3596

    CAS  PubMed  Google Scholar 

  14. Buratti E, Dork T, Zuccato E, Pagani F, Romano M, Baralle FE (2001) Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J 20:1774–1784

    Article  CAS  PubMed  Google Scholar 

  15. Wang IF, Reddy NM, Shen CK (2002) Higher order arrangement of the eukaryotic nuclear bodies. Proc Natl Acad Sci U S A 99:13583–13588

    Article  CAS  PubMed  Google Scholar 

  16. Strong MJ, Volkening K, Hammond R, Yang W, Strong W, Leystra-Lantz C, Shoesmith C (2007) TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol Cell Neurosci 35:320–327

    Article  CAS  PubMed  Google Scholar 

  17. Mackenzie IR, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ, Kwong LK, Forman MS, Ravits J, Stewart H et al (2007) Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 61:427–434

    Article  CAS  PubMed  Google Scholar 

  18. Guerreiro RJ, Schymick JC, Crews C, Singleton A, Hardy J, Traynor BJ (2008) TDP-43 is not a common cause of sporadic amyotrophic lateral sclerosis. PLoS ONE 3:e2450

    Article  PubMed  Google Scholar 

  19. Gijselinck I, Sleegers K, Engelborghs S, Robberecht W, Martin JJ, Vandenberghe R, Sciot R, Dermaut B, Goossens D, van der Zee J et al (2007) Neuronal inclusion protein TDP-43 has no primary genetic role in FTD and ALS. Neurobiol Aging 30:1329–1331

    Article  Google Scholar 

  20. Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672

    Article  CAS  PubMed  Google Scholar 

  21. Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, Bouchard JP, Lacomblez L, Pochigaeva K, Salachas F et al (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574

    Article  CAS  PubMed  Google Scholar 

  22. Kuhnlein P, Sperfeld AD, Vanmassenhove B, Van Deerlin V, Lee VM, Trojanowski JQ, Kretzschmar HA, Ludolph AC, Neumann M (2008) Two German kindreds with familial amyotrophic lateral sclerosis due to TARDBP mutations. Arch Neurol 65:1185–1189

    Article  PubMed  Google Scholar 

  23. Rutherford NJ, Zhang YJ, Baker M, Gass JM, Finch NA, Xu YF, Stewart H, Kelley BJ, Kuntz K, Crook RJ et al (2008) Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet 4:e1000193

    Article  PubMed  Google Scholar 

  24. Van Deerlin VM, Leverenz JB, Bekris LM, Bird TD, Yuan W, Elman LB, Clay D, Wood EM, Chen-Plotkin AS, Martinez-Lage M et al (2008) TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol 7:409–416

    Article  PubMed  Google Scholar 

  25. Yokoseki A, Shiga A, Tan CF, Tagawa A, Kaneko H, Koyama A, Eguchi H, Tsujino A, Ikeuchi T, Kakita A et al (2008) TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol 63:538–542

    Article  CAS  PubMed  Google Scholar 

  26. Daoud H, Valdmanis PN, Kabashi E, Dion P, Dupre N, Camu W, Meininger V, Rouleau GA (2009) Contribution of TARDBP mutations to sporadic amyotrophic lateral sclerosis. J Med Genet 46:112–114

    Article  CAS  PubMed  Google Scholar 

  27. Del Bo R, Ghezzi S, Corti S, Pandolfo M, Ranieri M, Santoro D, Ghione I, Prelle A, Orsetti V, Mancuso M et al (2009) TARDBP (TDP-43) sequence analysis in patients with familial and sporadic ALS: identification of two novel mutations. Eur J Neurol 16:727–732

    Article  PubMed  Google Scholar 

  28. Corrado L, Ratti A, Gellera C, Buratti E, Castellotti B, Carlomagno Y, Ticozzi N, Mazzini L, Testa L, Taroni F et al (2009) High frequency of TARDBP gene mutations in Italian patients with amyotrophic lateral sclerosis. Hum Mutat 30:688–694

    Article  CAS  PubMed  Google Scholar 

  29. Ayala YM, Zago P, D'Ambrogio A, Xu YF, Petrucelli L, Buratti E, Baralle FE (2008) Structural determinants of the cellular localization and shuttling of TDP-43. J Cell Sci 121:3778–3785

    Article  CAS  PubMed  Google Scholar 

  30. Winton MJ, Van Deerlin VM, Kwong LK, Yuan W, Wood EM, Yu CE, Schellenberg GD, Rademakers R, Caselli R, Karydas A et al (2008) A90V TDP-43 variant results in the aberrant localization of TDP-43 in vitro. FEBS Lett 582:2252–2256

    Article  CAS  PubMed  Google Scholar 

  31. Kovacs GG, Murrell JR, Horvath S, Haraszti L, Majtenyi K, Molnar MJ, Budka H, Ghetti B, Spina S (2009) TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea. Mov Disord (in press). doi:10.1002/mds.22697

  32. Benajiba L, Le Ber I, Camuzat A, Lacoste M, Thomas-Anterion C, Couratier P, Legallic S, Salachas F, Hannequin D, Decousus M et al (2009) TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration. Ann Neurol 65:470–473

    Article  CAS  PubMed  Google Scholar 

  33. Lemmens R, Race V, Hersmus N, Matthijs G, Van Den Bosch L, Van Damme P, Dubois B, Boonen S, Goris A, Robberecht W (2009) TDP-43 M311V mutation in familial amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 80:354–355

    Article  CAS  PubMed  Google Scholar 

  34. Buratti E, Brindisi A, Giombi M, Tisminetzky S, Ayala YM, Baralle FE (2005) TDP-43 binds heterogeneous nuclear ribonucleoprotein A/B through its C-terminal tail: an important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon 9 splicing. J Biol Chem 280:37572–37584

    Article  CAS  PubMed  Google Scholar 

  35. Mercado PA, Ayala YM, Romano M, Buratti E, Baralle FE (2005) Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene. Nucleic Acids Res 33:6000–6010

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was funded by The Wellcome Trust and the Motor Neurone Disease Association. WS was funded by the Jean Shanks Foundation. Our grateful thanks go also to those individuals who have donated samples for research purposes.

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Authors and Affiliations

  1. Academic Neurology Unit, Department of Neuroscience, Faculty of Medicine, Dentistry and Health, University of Sheffield, E-Floor, Medical School, Beech Hill Road, Sheffield, S10 2RX, UK

    Janine Kirby, Emily F. Goodall, William Smith, Rudo Masanzu, Judith A. Hartley, Rachel Hibberd, Hannah C. Hollinger, Christopher J. McDermott & Pamela J. Shaw

  2. Academic Neuropathology Unit, Department of Neuroscience, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, S10 2RX, UK

    J. Robin Highley, Stephen B. Wharton & Paul G. Ince

  3. Department of Neurology, The Medical School, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK

    Karen E. Morrison

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  1. Janine Kirby
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Correspondence to Janine Kirby.

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Authors Janine Kirby and Emily F. Goodall made an equal contribution.

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Kirby, J., Goodall, E.F., Smith, W. et al. Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis. Neurogenetics 11, 217–225 (2010). https://doi.org/10.1007/s10048-009-0218-9

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  • DOI: https://doi.org/10.1007/s10048-009-0218-9

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