Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17

Abstract

Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)1,2,3,4,5,6,7,8,9, historically termed Pick's disease10. Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics1,2,3,4,5,6,7,8,12. Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11; the tau gene also lies within this region. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5′ splice site of exon 10. The splice-site mutations all destabilize a potential stem–loop structure which is probably involved in regulating the alternative splicing of exon10 (ref. 13). This causes more frequent usage of the 5′ splice site and an increased proportion of tau transcripts that include exon 10. The increase in exon 10+ messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17 (refs 12, 14).

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Figure 1: tau mutations in FTDP-17.
Figure 3: 5′-splice-site mutations increase incorporation of tau exon 10 into artificial mRNAs.
Figure 2: tau exon-10 5′-splice-site mutations.

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Acknowledgements

This work was supported by an NINDS (RO1) grant to MH, an NIA (MCSDA) grant to T.L. and NIA (P50) grants to A.G. and J.C.M. and to M.H., J.H. and R.C.P. Additional support was provided by the Mayo Foundation (M.H., J.H.), the International Foundation for Alzheimer Research, the Dutch Brain Research Foundation (P.H.) and Judith Mason (P. Dodd). A.G. is the recipient of an NIH career development award (NIA). C.L.L. was a Washington University Alzheimer's Disease Research Center postdoctoral fellow. P.R. is the recipient of a TMG of EU grant. J.M.K. is the recipient of an NSADA award. T.L. is the recipient of Irving Scholar, NARSAD and Parkins's Disease Foundation awards. We thank the Mayo Clinic Molecular Biology Core Facility for sequencing and acknowledge the support of the Dutch Brain Bank (W.K., R.R.), the Michigan ADRC Brain Bank and the Columbia University Brain Bank. The participation of the families has been crucial.

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Correspondence to Mike Hutton or Peter Heutink.

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Hutton, M., Lendon, C., Rizzu, P. et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705 (1998). https://doi.org/10.1038/31508

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