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Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17


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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Figure 1: Null mutations in PGRN cause tau-negative FTD linked to chromosome 17.
Figure 2: Immunohistochemistry in FTD with PRGN mutations.
Figure 3: Mutant PGRN mRNAs with premature termination codons are degraded by nonsense-mediated decay.


  1. Brun, A. et al. Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester groups. J. Neurol. Neurosurg. Psychiatry 57, 416–418 (1994)

    Article  Google Scholar 

  2. Chow, T. W., Miller, B. L., Hayashi, V. N. & Geschwind, D. H. Inheritance of frontotemporal dementia. Arch. Neurol. 56, 817–822 (1999)

    Article  CAS  Google Scholar 

  3. Hutton, M. et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393, 702–705 (1998)

    Article  ADS  CAS  Google Scholar 

  4. Ingram, E. M. & Spillantini, M. G. Tau gene mutations: dissecting the pathogenesis of FTDP-17. Trends Mol. Med. 8, 555–562 (2002)

    Article  CAS  Google Scholar 

  5. Rademakers, R. et al. Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval. Mol. Psychiatry 7, 1064–1074 (2002)

    Article  CAS  Google Scholar 

  6. Rosso, S. M. et al. Familial frontotemporal dementia with ubiquitin-positive inclusions is linked to chromosome 17q21–22. Brain 124, 1948–1957 (2001)

    Article  CAS  Google Scholar 

  7. Lendon, C. L. et al. Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21–22. Neurology 50, 1546–1555 (1998)

    Article  CAS  Google Scholar 

  8. Kertesz, A. et al. Familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions. Neurology 54, 818–827 (2000)

    Article  CAS  Google Scholar 

  9. Froelich, S. et al. Mapping of a disease locus for familial rapidly progressive frontotemporal dementia to chromosome 17q12–21. Am. J. Med. Genet. 74, 380–385 (1997)

    Article  CAS  Google Scholar 

  10. Bird, T. D. et al. Chromosome 17 and hereditary dementia: linkage studies in three non-Alzheimer families and kindreds with late-onset FAD. Neurology 48, 949–954 (1997)

    Article  CAS  Google Scholar 

  11. van der Zee, J. et al. A Belgian ancestral haplotype harbours a highly prevalent mutation for 17q21-linked tau-negative FTLD. Brain 129, 841–852 (2006)

    Article  Google Scholar 

  12. Mackenzie, I. R. et al. A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17. Brain 129, 853–867 (2006)

    Article  Google Scholar 

  13. Rademakers, R. et al. In IPSEN Meeting Research and Perspectives in Alzheimer's Disease: Genotype–Proteotype–Phenotype Relationships in Neurodegenerative Diseases (ed. Cummings, J.) 117–137 (Springer, Paris, 2005)

    Google Scholar 

  14. He, Z. & Bateman, A. Progranulin (granulin–epithelin precursor, PC-cell-derived growth factor, acrogranin) mediates tissue repair and tumorigenesis. J. Mol. Med. 81, 600–612 (2003)

    Article  CAS  Google Scholar 

  15. Malaspina, A., Kaushik, N. & de Belleroche, J. Differential expression of 14 genes in amyotrophic lateral sclerosis spinal cord detected using gridded cDNA arrays. J. Neurochem. 77, 132–145 (2001)

    Article  CAS  Google Scholar 

  16. Baker, C. A. & Manuelidis, L. Unique inflammatory RNA profiles of microglia in Creutzfeldt–Jakob disease. Proc. Natl Acad. Sci. USA 100, 675–679 (2003)

    Article  ADS  CAS  Google Scholar 

  17. Neary, D., Snowden, J. S. & Mann, D. M. Classification and description of frontotemporal dementias. Ann. NY Acad. Sci. 920, 46–51 (2000)

    Article  ADS  CAS  Google Scholar 

  18. Trojanowski, J. Q. & Dickson, D. Update on the neuropathological diagnosis of frontotemporal dementias. J. Neuropathol. Exp. Neurol. 60, 1123–1126 (2001)

    Article  CAS  Google Scholar 

  19. Mackenzie, I. R. & Feldman, H. H. Ubiquitin immunohistochemistry suggests classic motor neuron disease, motor neuron disease with dementia, and frontotemporal dementia of the motor neuron disease type represent a clinicopathologic spectrum. J. Neuropathol. Exp. Neurol. 64, 730–739 (2005)

    Article  Google Scholar 

  20. Foster, N. L. et al. Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Ann. Neurol. 41, 706–715 (1997)

    Article  CAS  Google Scholar 

  21. Mackenzie, I. R. & Feldman, H. Neuronal intranuclear inclusions distinguish familial FTD–MND type from sporadic cases. Acta Neuropathol. (Berl.) 105, 543–548 (2003)

    Google Scholar 

  22. Cruts, M. et al. Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region. Hum. Mol. Genet. 14, 1753–1762 (2005)

    Article  CAS  Google Scholar 

  23. Cruts, M. et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature advance online publication, doi:10.1038/nature05017 (16 July 2006)

  24. Maquat, L. E. Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nature Rev. Mol. Cell Biol. 5, 89–99 (2004)

    Article  CAS  Google Scholar 

  25. Daniel, R., He, Z., Carmichael, K. P., Halper, J. & Bateman, A. Cellular localization of gene expression for progranulin. J. Histochem. Cytochem. 48, 999–1009 (2000)

    Article  CAS  Google Scholar 

  26. Capsoni, S. et al. Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice. Proc. Natl Acad. Sci. USA 97, 6826–6831 (2000)

    Article  ADS  CAS  Google Scholar 

  27. Salehi, A., Delcroix, J. D. & Swaab, D. F. Alzheimer's disease and NGF signaling. J. Neural Transm. 111, 323–345 (2004)

    Article  CAS  Google Scholar 

  28. Lu, R. & Serrero, G. Mediation of estrogen mitogenic effect in human breast cancer MCF-7 cells by PC-cell-derived growth factor (PCDGF/granulin precursor). Proc. Natl Acad. Sci. USA 98, 142–147 (2001)

    Article  ADS  CAS  Google Scholar 

  29. Tangkeangsirisin, W. & Serrero, G. PC cell-derived growth factor (PCDGF/GP88, progranulin) stimulates migration, invasiveness and VEGF expression in breast cancer cells. Carcinogenesis 25, 1587–1592 (2004)

    Article  CAS  Google Scholar 

  30. Greenway, M. J. et al. ANG mutations segregate with familial and ‘sporadic’ amyotrophic lateral sclerosis. Nature Genet. 38, 411–413 (2006)

    Article  CAS  Google Scholar 

  31. He, Z., Ong, C. H., Halper, J. & Bateman, A. Progranulin is a mediator of the wound response. Nature Med. 9, 225–229 (2003)

    Article  CAS  Google Scholar 

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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.

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Correspondence to Ian R. Mackenzie or Mike Hutton.

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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).

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