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Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006 Aug 24;442(7105):916-9. PubMed.
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Institute of Neurology, UCL
The identification of progranulin mutations by Baker and colleagues is a major advance in our understanding of frontal temporal dementia (FTD). The work by both Baker and Cruts and their colleagues shows that loss of progranulin function is a major cause of FTD, at least in some populations. These findings are remarkable for several reasons: first, this is the first simple loss-of-function autosomal dominant disease; second, it suggests that the genetic linkage of two FTD loci with similar clinical features, but different pathologies, close to the same locus was just a confusing coincidence. Third, it will undoubtedly spawn a huge amount of effort to define the limits of the phenotype and to elucidate its precise function in the CNS. It will also be interesting to see whether other diseases with ubiquitin inclusions will share related pathogenic mechanisms.View all comments by John Hardy
University of Pennsylvania
These studies are spectacular advances in FTD research that open up new avenues for understanding mechanisms of FTLD-U. Notably, since progranulin proteins, or derivatives thereof, were not found in the ubiquitin inclusions of these FTLD-U disorders, it will be important to identify the ubiquitinated disease protein(s) that form these hallmark lesions of FTLD-U.View all comments by Virginia Lee
University of Western Ontario
Both of these papers represent a significant discovery of a novel mutation on progranulin, a protein with no known CNS function. It is a known growth factor in vasculo and tumorigenesis, and it may turn out to have nerve growth factor properties as well; therefore, it is reasonable to postulate that a molecular deficit caused by its mutation could produce neurodegenerative disease such as frontotemporal dementia (FTD). We published the first chromosome 17-linked ubiquitin-positive family from Ontario in 2000 and the first intranuclear ubiquitin-positive inclusions in this and other families (1,2), but these genetic teams deserve credit for finding the mutation.
What is extraordinary is that progranulin is very close to the tau gene on chromosome 17, the known culprit in the mutated form in FTD linked to 17. How the two different genes interact, if at all, to cause a very similar illness is yet to be determined. The relationship of progranulin mechanisms to chromosome 9-linked cases and the valosin mutation with FTD and myopathy also deserves attention.
Kertesz A, Kawarai T, Rogaeva E, St George-Hyslop P, Poorkaj P, Bird TD, Munoz DG. Familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions. Neurology. 2000 Feb 22;54(4):818-27. PubMed.
Woulfe J, Kertesz A, Munoz DG. Frontotemporal dementia with ubiquitinated cytoplasmic and intranuclear inclusions. Acta Neuropathol. 2001 Jul;102(1):94-102. PubMed.View all comments by Andrew Kertesz
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