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Recent origin and spread of a common Welsh MAPT splice mutation causing frontotemporal lobar degeneration

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Abstract

IVS10+16C>T is the most prevalent mutation in the microtubule-associated protein tau gene (MAPT) causing frontotemporal lobar degeneration (FTLD) in populations of British descent. A highly conserved 17q21 haplotype was identified in IVS10+16C>T chromosomes from North Wales, Greater Manchester and the London areas of the UK, Australia, and the USA, suggesting the occurrence of a common founder effect. To test this hypothesis, the age of the mutation was estimated by parametric and Bayesian analysis of linkage disequilibrium's decay over generations, and the results were compared with historical and geographical data on FTLD families. The inferred age (23 generations; 95% confidence interval, 9–74 generations) dates the most recent common ancestor of IVS10+16C>T chromosomes before Welsh people started emigrating to the USA and Australia, where they introduced the mutation. The identification of a cohort of FTLD families with a homogeneous genetic background within and around the MAPT locus will further the investigation of the different clinical and pathological presentations of patients with identical MAPT mutations.

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References

  1. Lee VM, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159. doi:10.1146/annurev.neuro.24.1.1121

    Article  CAS  PubMed  Google Scholar 

  2. Williams DR (2006) Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau. Intern Med J 36:652–660. doi:10.1111/j.1445-5994.2006.01153.x

    Article  CAS  PubMed  Google Scholar 

  3. Foster NL, Wilhelmsen K, Sima AA, Jones MZ, D'Amato CJ, Gilman S (1997) Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Ann Neurol 41:706–715. doi:10.1002/ana.410410606

    Article  CAS  PubMed  Google Scholar 

  4. 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, Petra 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 JBJ, Peter RPR, 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 

  5. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD (1998) Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 43:815–826. doi:10.1002/ana.410430617

    Article  CAS  PubMed  Google Scholar 

  6. Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B (1998) Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A 95:7737–7741. doi:10.1073/pnas.95.13.7737

    Article  CAS  PubMed  Google Scholar 

  7. Mann DM, South PW, Snowden JS, Neary D (1993) Dementia of frontal lobe type: neuropathology and immunohistochemistry. J Neurol Neurosurg Psychiatry 56:605–614. doi:10.1136/jnnp. 56.6.605

    Article  CAS  PubMed  Google Scholar 

  8. Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546–1554

    CAS  PubMed  Google Scholar 

  9. Pickering-Brown SM, Richardson AM, Snowden JS, McDonagh AM, Burns A, Braude W, Baker M, Liu WK, Yen SH, Hardy J, Hutton M, Davies Y, Allsop D, Craufurd D, Neary D, Mann DM (2002) Inherited frontotemporal dementia in nine British families associated with intronic mutations in the tau gene. Brain 125(Pt 4):732–751. doi:10.1093/brain/awf069

    Article  CAS  PubMed  Google Scholar 

  10. Saito Y, Geyer A, Sasaki R, Kuzuhara S, Nanba E, Miyasaka T, Suzuki K, Murayama S (2002) Early-onset, rapidly progressive familial tauopathy with R406W mutation. Neurology 58:811–813

    CAS  PubMed  Google Scholar 

  11. Kobayashi T, Mori H, Okuma Y, Dickson DW, Cookson N, Tsuboi Y, Motoi Y, Tanaka R, Miyashita N, Anno M, Narabayashi H, Mizuno Y (2002) Contrasting genotypes of the tau gene in two phenotypically distinct patients with P301L mutation of frontotemporal dementia and parkinsonism linked to chromosome 17. J Neurol 249:669–675. doi:10.1007/s00415-002-0687-3

    Article  PubMed  Google Scholar 

  12. Stevens M, van Duijn CM, Kamphorst W, de Knijff P, Heutink P, van Gool WA, Scheltens P, Ravid R, Oostra BA, Niermeijer MF, van Swieten JC (1998) Familial aggregation in frontotemporal dementia. Neurology 50:1541–1545

    CAS  PubMed  Google Scholar 

  13. Sahara N, Maeda S, Takashima A (2008) Tau oligomerization: a role for tau aggregation intermediates linked to neurodegeneration. Curr Alzheimer Res 5:591–598. doi:10.2174/156720508786898442

    Article  CAS  PubMed  Google Scholar 

  14. Alonso AC, Li B, Grundke-Iqbal I, Iqbal K (2008) Mechanism of tau-induced neurodegeneration in Alzheimer disease and related tauopathies. Curr Alzheimer Res 5:375–384. doi:10.2174/156720508785132307

    Article  CAS  PubMed  Google Scholar 

  15. Barten DM, Albright CF (2008) Therapeutic strategies for Alzheimer's disease. Mol Neurobiol 37:171–186. doi:10.1007/s12035-008-8031-2

    Article  CAS  PubMed  Google Scholar 

  16. Sigurdsson EM (2008) Immunotherapy targeting pathological tau protein in Alzheimer's disease and related tauopathies. J Alzheimers Dis 15:157–168

    CAS  PubMed  Google Scholar 

  17. Rizzu P, Van Swieten JC, Joosse M, Hasegawa M, Stevens M, Tibben A, Niermeijer MF, Hillebrand M, Ravid R, Oostra BA, Goedert M, van Duijn CM, Heutink P (1999) High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am J Hum Genet 64:414–421. doi:10.1086/302256

    Article  CAS  PubMed  Google Scholar 

  18. Rademakers R, Cruts M, van Broeckhoven C (2004) The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum Mutat 24:277–295. doi:10.1002/humu.20086

    Article  CAS  PubMed  Google Scholar 

  19. Stanford PM, Brooks WS, Teber ET, Hallupp M, McLean C, Halliday GM, Martins RN, Kwok JB, Schofield PR (2004) Frequency of tau mutations in familial and sporadic frontotemporal dementia and other tauopathies. J Neurol 251:1098–1104. doi:10.1007/s00415-004-0489-x

    Article  CAS  PubMed  Google Scholar 

  20. Poorkaj P, Grossman M, Steinbart E, Payami H, Sadovnick A, Nochlin D, Tabira T, Trojanowski JQ, Borson S, Galasko D, Reich S, Quinn B, Schellenberg G, Bird TD (2001) Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia. Arch Neurol 58:383–387. doi:10.1001/archneur.58.3.383

    Article  CAS  PubMed  Google Scholar 

  21. Janssen JC, Warrington EK, Morris HR, Lantos P, Brown J, Revesz T, Wood N, Khan MN, Cipolotti L, Fox NC, Rossor MN (2002) Clinical features of frontotemporal dementia due to the intronic tau 10(+16) mutation. Neurology 58:1161–1168

    CAS  PubMed  Google Scholar 

  22. Lantos PL, Cairns NJ, Khan MN, King A, Revesz T, Janssen JC, Morris H, Rossor MN (2002) Neuropathologic variation in frontotemporal dementia due to the intronic tau 10(+16) mutation. Neurology 58:1169–1175

    CAS  PubMed  Google Scholar 

  23. Doran M, du Plessis DG, Ghadiali EJ, Mann DMA, Pickering-Brown S, Larner AJ (2007) Familial early-onset dementia with tau intron 10 +16 mutation with clinical features similar to those of Alzheimer disease. Arch Neurol 64:1535–1539. doi:10.1001/archneur.64.10.1535

    Article  PubMed  Google Scholar 

  24. Grover A, Houlden H, Baker M, Adamson J, Lewis J, Prihar G, Pickering-Brown S, Duff K, Hutton M (1999) 5' splice site mutations in tau associated with the inherited dementia FTDP-17 affect a stem-loop structure that regulates alternative splicing of exon 10. J Biol Chem 274:15134–15143. doi:10.1074/jbc.274.21.15134

    Article  CAS  PubMed  Google Scholar 

  25. Chang E, Kim S, Yin H, Nagaraja HN, Kuret J (2008) Pathogenetic missense MAPT mutations differentially modulate tau aggregation propensity at nucleation and extension steps. J Neurochem 197:1113–1123

    Google Scholar 

  26. Pickering-Brown S, Baker M, Bird T, Trojanowski J, Lee V, Morris H, Rossor M, Janssen JC, Neary D, Craufurd D, Richardson A, Snowden J, Hardy J, Mann D, Hutton M (2004) Evidence of a founder effect in families with frontotemporal dementia that harbor the tau +16 splice mutation. Am J Med Genet 125B:79–82. doi:10.1002/ajmg.b.20083

    Article  PubMed  Google Scholar 

  27. Labuda D, Zietkiewicz LM (1997) The genetic clock and the age of the founder effect in growing populations: a lesson from French Canadians and Ashkenazim. Am J Hum Genet 61:768–771. doi:10.1016/S0002-9297(07)64341-9

    Article  CAS  PubMed  Google Scholar 

  28. Risch N, de Leon D, Ozelius L, Kramer P, Almasy L, Singer B, Fahn S, Breakefield X, Bressman S (1995) Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews and their recent descent from a small founder population. Nat Genet 9:152–159. doi:10.1038/ng0295-152

    Article  CAS  PubMed  Google Scholar 

  29. Reich DE, Goldstein DB (1999) Estimating the age of mutations using variation at linked markers. In: Goldstein GB, Schlötterer C (eds) Microsatellites: evolution and applications. Oxford University Press, Oxford, pp 129–138

    Google Scholar 

  30. Rannala B, Reeve JP (2001) High-resolution multipoint linkage-disequilibrium mapping in the context of a human genome sequence. Am J Hum Genet 69:159–178. doi:10.1086/321279

    Article  CAS  PubMed  Google Scholar 

  31. Génin E, Tullio-Pelet A, Begeot F, Lyonnet S, Abel L (2004) Estimating the age of rare disease mutations: the example of Triple-A syndrome. J Med Genet 41:445–449. doi:10.1136/jmg.2003.017962

    Article  PubMed  Google Scholar 

  32. Williams J (ed) (2001) Digest of Welsh historical statistics: Population, 1570–1974. UK Data Archive (Study No 4093), Colchester, Essex

  33. Dark F (1997) A family with autosomal dominant, non-Alzheimer's presenile dementia. Aust N Z J Psychiatry 31:139–144. doi:10.3109/00048679709073812

    Article  CAS  PubMed  Google Scholar 

  34. Williams D (1935) Some figures relating to emigration from Wales. Bull Board Celtic Stud 7:395–415

    Google Scholar 

  35. Pickering-Brown SM, Rollinson S, Du Plessis D, Morrison KE, Varma A, Richardson AM, Neary D, Snowden JS, Mann DM (2008) Frequency and clinical characteristics of progranulin mutation carriers in the Manchester frontotemporal lobar degeneration cohort: comparison with patients with MAPT and no known mutations. Brain 131:721–731. doi:10.1093/brain/awm331

    Article  PubMed  Google Scholar 

  36. Garrard P, Carroll E (2007) Familial early-onset dementia with tau intron 10 + 16 mutation with clinical features similar to those of Alzheimer disease. Arch Neurol 64:1535–1539. doi:10.1001/archneur.64.10.1535

    Article  Google Scholar 

  37. Goedert M, Spillantini MG, Crowther RA, Chen SG, Parchi P, Tabaton M, Lanska DJ, Markesbery WR, Wilhelmsen KC, Dickson DW, Petersen RB, Gambetti P (1999) Tau gene mutation in familial progressive subcortical gliosis. Nat Med 5:454–457. doi:10.1038/7454

    Article  CAS  PubMed  Google Scholar 

  38. Bengtsson BO, Thomson G (1981) Measuring the strength of associations between HLA antigens and diseases. Tissue Antigens 18:356–363. doi:10.1111/j.1399-0039.1981.tb01404.x

    Article  CAS  PubMed  Google Scholar 

  39. Kong A, Gudbjartsson DF, Sainz J, Jonsdottir GM, Gudjonsson SA, Richardsson B, Sigurdardottir S, Barnard J, Hallbeck B, Masson G, Shlien A, Palsson ST, Frigge ML, Thorgeirsson TE, Gulcher JR, Stefansson K (2002) A high-resolution recombination map of the human genome. Nat Genet 31:241–247

    CAS  PubMed  Google Scholar 

Electronic-Database Information

  1. Online Mendelian Inheritance in Man (OMIM). http://www.ncbi.nlm.nih.gov/sites/entrez (for FTDP-17 [MIM 600274] and microtubule-associated protein tau [MIM 157140])

  2. Alzheimer Disease & Frontotemporal Dementia Mutation Database. http://www.molgen.ua.ac.be/Admutations

  3. DMLE+ Linkage Disequilibrium Mapping Software. http://dmle.org/

  4. Centre d'Études du Polymorphisme Humain. http://www.cephb.fr/ceph-genethon-map.html

  5. UCSC Genome Bioinformatics. http://genome.ucsc.edu/

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Acknowledgments

This work was supported in part by research grants from the Italian Ministry of University and Scientific and Technological Research (MURST-FIRB), the Cariplo Foundation (both to R.C.), and the Medical Research Council, UK (to S.P.B.). The authors thank Emmanuelle Genin (Villejuif, France) for providing ESTIAGE C-language source and Emanuele Ortoleva (Milan, Italy) for Windows compilation of the files. The authors wish also to thank the following individuals for supplying DNA for the original analysis of the haplotypes: Tom Bird (Geriatrics Research Education Clinical Center, Seattle, USA), John Trojanowski and Virginia Lee (University of Pennsylvania School of Medicine, Philadelphia, USA), and Huw Morris, Martin Rossor, and John Jannsen (Institute of Neurology, London, UK).

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Authors and Affiliations

  1. Laboratory of Human Molecular Biology and Genetics, Catholic University of the Sacred Heart, Piazza Buonarroti 30, 20145, Milan, Italy

    Roberto Colombo & Daniela Tavian

  2. National Institute of Molecular Genetics (INGM), Milan, Italy

    Roberto Colombo & Daniela Tavian

  3. Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, USA

    Matthew C. Baker

  4. Clinical Neuroscience Research Group, Faculty of Medical and Human Sciences, University of Manchester, 2.014 AV Hill Building, Oxford Road, Manchester, M13 9PT, UK

    Anna M. T. Richardson, Julie S. Snowden, David Neary, David M. A. Mann & Stuart M. Pickering-Brown

  5. Greater Manchester Neurosciences Centre, Hope Hospital, Salford, UK

    Anna M. T. Richardson, Julie S. Snowden, David Neary & David M. A. Mann

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  1. Roberto Colombo
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  2. Daniela Tavian
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Correspondence to Roberto Colombo or Stuart M. Pickering-Brown.

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Colombo, R., Tavian, D., Baker, M.C. et al. Recent origin and spread of a common Welsh MAPT splice mutation causing frontotemporal lobar degeneration. Neurogenetics 10, 313–318 (2009). https://doi.org/10.1007/s10048-009-0189-x

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  • DOI: https://doi.org/10.1007/s10048-009-0189-x

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