, Volume 10, Issue 4, pp 313–318 | Cite as

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

  • Roberto ColomboEmail author
  • Daniela Tavian
  • Matthew C. Baker
  • Anna M. T. Richardson
  • Julie S. Snowden
  • David Neary
  • David M. A. Mann
  • Stuart M. Pickering-BrownEmail author
Original Article


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.


Frontotemporal lobar degeneration Microtubule-associated tau protein IVS10+16C>T MAPT mutation Linkage disequilibrium Founder effect Age of mutation 



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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Electronic-Database Information

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    Online Mendelian Inheritance in Man (OMIM). (for FTDP-17 [MIM 600274] and microtubule-associated protein tau [MIM 157140])
  2. 41.
    Alzheimer Disease & Frontotemporal Dementia Mutation Database.
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    DMLE+ Linkage Disequilibrium Mapping Software.
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    Centre d'Études du Polymorphisme Humain.
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    UCSC Genome Bioinformatics.

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Roberto Colombo
    • 1
    • 2
    Email author
  • Daniela Tavian
    • 1
    • 2
  • Matthew C. Baker
    • 3
  • Anna M. T. Richardson
    • 4
    • 5
  • Julie S. Snowden
    • 4
    • 5
  • David Neary
    • 4
    • 5
  • David M. A. Mann
    • 4
    • 5
  • Stuart M. Pickering-Brown
    • 4
    Email author
  1. 1.Laboratory of Human Molecular Biology and GeneticsCatholic University of the Sacred HeartMilanItaly
  2. 2.National Institute of Molecular Genetics (INGM)MilanItaly
  3. 3.Department of NeuroscienceMayo Clinic College of MedicineJacksonvilleUSA
  4. 4.Clinical Neuroscience Research Group, Faculty of Medical and Human SciencesUniversity of ManchesterManchesterUK
  5. 5.Greater Manchester Neurosciences CentreHope HospitalSalfordUK

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