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

Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)1,2,3,4,5,6,7,8,9, historically termed Pick's disease10. 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 characteristics1,2,3,4,5,6,7,8,12. 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 (ref. 13). 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 (refs 12, 14).