Abstract
The microtubule-associated protein tau (encoded by MAPT) and several tau kinases have been implicated in neurodegeneration, but only MAPT has a proven role in disease. We identified mutations in the gene encoding tau tubulin kinase 2 (TTBK2) as the cause of spinocerebellar ataxia type 11. Affected brain tissue showed substantial cerebellar degeneration and tau deposition. These data suggest that TTBK2 is important in the tau cascade and in spinocerebellar degeneration.
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References
Schols, L. et al. Lancet Neurol. 3, 291–304 (2004).
Harding, A.E. Brain 105, 1–28 (1982).
Ranum, L.P. & Day, J.W. Curr. Opin. Genet. Dev. 12, 266–271 (2002).
Orr, H.T. & Zoghbi, H.Y. Annu. Rev. Neurosci. 30, 575–621 (2007).
Worth, P.F. et al. Am. J. Hum. Genet. 65, 420–426 (1999).
Baker, M. et al. Nature 442, 916–919 (2006).
Riudavets, M.A. et al. J. Neuropathol. Exp. Neurol. 65, 1143–1148 (2006).
Mann, D.M. et al. Neuropathol. Appl. Neurobiol. 16, 17–25 (1990).
Mukaetova-Ladinska, E.B. et al. Am. J. Pathol. 143, 565–578 (1993).
Ballatore, C., Lee, V.M. & Trojanowski, J.Q. Nat. Rev. Neurosci. 8, 663–672 (2007).
Takahashi, M. et al. FEBS Lett. 372, 59–64 (1995).
Sato, S. et al. J. Neurochem. 98, 1573–1584 (2006).
Kitano-Takahashi, M. et al. Acta Crystallograph. Sect. F Struct. Biol. Cryst. Commun. 63, 602–604 (2007).
Noble, W. et al. Proc. Natl. Acad. Sci. USA 102, 6990–6995 (2005).
Kraemer, B.C. et al. Hum. Mol. Genet. 15, 1483–1496 (2006).
Acknowledgements
We are grateful to the UK Medical Research Council (MRC) for their support of the entire project: H.H. holds an MRC clinician scientist fellowship. We also thank the European Commission (EUROSCA) for supporting the initial work. This work was undertaken at University College London Hospital/University College London, which received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centers funding scheme. This work was supported in part by the Intramural Program of the US National Institute on Aging, National Institutes of Health, Department of Health and Human Services. We thank S. Schorge for her helpful comments on the paper as well as the members of the affected families that we studied and the organization Ataxia UK for their continued support and assistance with our work.
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H.H. planned and supervised the project. J.J. carried out the candidate gene sequencing and genetic analysis. C.G.-T., P.W., P.G. and N.W.W. performed phenotypic assessment of family members. P.W. and M.B.D. carried out the genetic linkage analysis. T.L. and H.H. carried out the in situ hybridization. T.L. prepared the pathology material to be analyzed by D.A.H., J.H. and T.R. D.H. and A.B.S. contributed to the writing of the manuscript and carried out whole-genome arrays. H.H. and N.W.W. wrote the manuscript.
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Houlden, H., Johnson, J., Gardner-Thorpe, C. et al. Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11. Nat Genet 39, 1434–1436 (2007). https://doi.org/10.1038/ng.2007.43
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DOI: https://doi.org/10.1038/ng.2007.43
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