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 inh erited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)(1-9), historically termed Pick's disease(10 ). 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 it s quantity (or severity) and characteristics(1-8,12). 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 sequ enced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon in. The splice-site mutations all destabilize a potential stem-lo op 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 tan transcripts that incl ude exon 10. The increase in exon 10(+) messenger RNA will increase th e proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families w ith FTDP-17 (refs 12, 14).