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

Topic: Brain proteins, microglia and lab models

Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 years. A large proportion of FTD patients (35-50%) have a family history of dementia, consistent with a strong genetic component to the disease. 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). The neuropathology of patients with defined MAPT mutations is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau. 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 pathology. In contrast, these patients have ubiquitin (ub)-immunoreactive neuronal cytoplasmic inclusions and characteristic lentiform ub-immunoreactive neuronal intranuclear inclusions. 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 inflammation. PGRN has also been strongly linked to tumorigenesis. Moreover, PGRN expression is increased in activated microglia in many neurodegenerative diseases including Creutzfeldt-Jakob disease, motor neuron disease and Alzheimer's disease. Our results identify mutations in PGRN as a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival.

Key findings

• 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 pathology.
• Our results identify mutations in PGRN as a cause of neurodegenerative disease and indicate the importance of PGRN function for neuronal survival.

Why it matters

Some families with frontotemporal dementia (FTD) are linked to the same part of chromosome 17 as the tau gene, yet have no tau-gene mutation and no tau deposits in the brain; this study reports that in these families FTD is caused by mutations in progranulin, a nearby gene for a secreted growth factor, mutations "likely to create null alleles". The authors conclude that this identifies progranulin mutations "as a cause of neurodegenerative disease" and points to the protein's importance for nerve-cell survival. It explains a genetic cause of one form of FTD; its only Alzheimer's link is that progranulin levels rise in activated immune cells in the brain in Alzheimer's and other diseases, and it is not a treatment, cure or prevention.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/nature05016
• PubMed: 16862116
• Original source →

May need a subscription OpenAlex found no free copy of the full text (checked 6 Feb 1020), so the publisher may charge for it. The PubMed abstract is free.

@article{baker2006-16862116,
  author  = {Baker, M. and Mackenzie, I. R. and Pickering-Brown, S. M. and Gass, J. and Rademakers, R. and Lindholm, C. and Snowden, J. and Adamson, J. and others},
  title   = {{Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17}},
  journal = {Nature},
  year    = {2006},
  doi     = {10.1038/nature05016},
  pmid    = {16862116},
  url     = {https://doi.org/10.1038/nature05016}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17 Nature · 1998-06-01 · usefulness score 64/100 · Lewy body dementia
• Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 Nature · 2006-07-16 · usefulness score 64/100 · Lewy body dementia
• Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups. Journal of Neurology Neurosurgery & Psychiatry · 1994-04-01 · usefulness score 53/100 · Getting a diagnosis
• Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Conference Participants Annals of neurology · 1997-06-01 · usefulness score 51/100 · Lewy body dementia
• Familial frontotemporal dementia with ubiquitin-positive inclusions is linked to chromosome 17q21-22 Brain : a journal of neurology · 2001-10-01 · usefulness score 45/100 · Digital health tools

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• Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements Proceedings of the National Academy of Sciences of the United States of America · 1999-05-01 · usefulness score 51/100
• Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17 Proceedings of the National Academy of Sciences of the United States of America · 1998-10-01 · usefulness score 51/100
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• Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics 2012 · Getting a diagnosis
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• Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure 2001 · Lewy body dementia
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