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

M Hutton, CL Lendon, P Rizzu, M Baker, S Froelich… - Nature, 1998 - nature.com
M Hutton, CL Lendon, P Rizzu, M Baker, S Froelich, H Houlden, S Pickering-Brown
Nature, 1998nature.com
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 …
Abstract
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 (, ).
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