Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17

Topic: Brain proteins, microglia and lab models

Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's disease. Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics. Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11; the tau gene also lies within this region. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon 10. The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10. This causes more frequent usage of the 5' splice site and an increased proportion of tau transcripts that include exon 10. The increase in exon 10+ messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17.

Key findings

• Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11; the tau gene also lies within this region.
• We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon 10.
• The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10.
• This causes more frequent usage of the 5' splice site and an increased proportion of tau transcripts that include exon 10.
• The increase in exon 10+ messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17.

Why it matters

This study identified missense and splice-site mutations in the tau gene in families with the inherited dementia FTDP-17. It concerns the genetic cause of that inherited dementia and does not test any treatment, cure or prevention for Alzheimer's disease.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/31508
• PubMed: 9641683
• 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{hutton1998-9641683,
  author  = {Hutton, M. and Lendon, C. L. and Rizzu, P. and Baker, M. and Froelich, S. and Houlden, H. and Pickering-Brown, S. and Chakraverty, S. and others},
  title   = {{Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17}},
  journal = {Nature},
  year    = {1998},
  doi     = {10.1038/31508},
  pmid    = {9641683},
  url     = {https://doi.org/10.1038/31508}
}

Studies this one cites

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

• 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
• Hereditary frontotemporal dementia is linked to chromosome 17q21-q22: a genetic and clinicopathological study of three Dutch families Annals of neurology · 1997-02-01 · usefulness score 46/100 · 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
• Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly FEBS letters · 1998-10-01 · usefulness score 49/100
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