Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years1. A large proportion of FTD patients (35–50%) have a family history of dementia, consistent with a strong genetic component to the disease2. In 1998, mutations in the gene encoding the microtubule-associated protein tau (MAPT) were shown to cause familial FTD with parkinsonism linked to chromosome 17q21 (FTDP-17)3. The neuropathology of patients with defined MAPT mutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau3,4. However, in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21 (D17S1787–D17S806), mutations in MAPT have not been found and the patients consistently lack tau-immunoreactive inclusion pathology5,6,7,8,9,10,11,12. In contrast, these patients have ubiquitin (ub)-immunoreactive neuronal cytoplasmic inclusions and characteristic lentiform ub-immunoreactive neuronal intranuclear inclusions11,12,13. Here we demonstrate that in these families, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles. PGRN is located 1.7 Mb centromeric of MAPT on chromosome 17q21.31 and encodes a 68.5-kDa secreted growth factor involved in the regulation of multiple processes including development, wound repair and inflammation14. PGRN has also been strongly linked to tumorigenesis14. Moreover, PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt–Jakob disease, motor neuron disease and Alzheimer's disease15,16. Our results identify mutations in PGRN as a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival.
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We thank the FTD research team at Vancouver Coastal Health and the University of British Columbia, and particularly G. Y. R. Hsiung, for identification and follow-up of FTD families; D. Warden, P. Whitbread and E. King (OPTIMA project, Oxford, UK) for assisting with collection of UBC17 family samples; J. Chow (Department of Pathology, University of British Columbia) for help in performing the PGRN immunohistochemistry; and M. Yue, J. Gonzales (Mayo Clinic), T. de Pooter and M. Van den Broeck (University of Antwerp) for technical support. This research was funded as part of the Mayo Clinic ADRC grant from the National Institute on Aging (to M.H.), the Mayo Foundation (M.H.), and the Robert and Clarice Smith Fellowship program (to S.M.). I.R.M. and H.F. were funded by the Canadian Institutes of Health research operating grant. S.M.P.-B. received grants from the Medical Research Council (UK) and the Motor Neuron Disease Association. R.R. is a postdoctoral fellow of the Fund for Scientific Research Flanders and a visiting scientist from the Neurodegenerative Brain Diseases Group of the Department of Molecular Genetics, VIB, University of Antwerp, Belgium. Finally, we acknowledge and thank the families who contributed samples, as without them this study would not have been possible.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
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Baker, M., Mackenzie, I., Pickering-Brown, S. et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442, 916–919 (2006). https://doi.org/10.1038/nature05016
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