A novel mutation at position+12 in the intron following exon 10 of the taugene in familial frontotemporal dementia (FTD-Kumamoto)

Exonic and intronic mutations in the tau gene cause familiar frontotemporal dementia and parkinsonism linked to chromosome 17. Here, we describe a new mutation, consisting of a C-to-T transition at position +12 of the intron following exon 10 of the tau gene in the Kumamoto pedigree, showing frontot emporal dementia. The mutation caused a marked reduction in melting tempera ture of the tau exon 10-splicing regulatory element RNA and a targe increas e in exon 10-containing transcripts. Brain tissue from affected individuals showed an abnormal preponderance of exon 10-containing transcripts that wa s reflected at the protein level by an overproduction of tau isoforms with four microtubule-binding repeats. Immunostaining revealed the presence of t au aggregates in degenerating neurons and glial cells. isolated tau filamen ts had a twisted ribbon-like morphology and were made of hyperphosphorylate d four-repeat tau isoforms. The additional mutation located close to the sp lice-donor site of the intron following exon 10 of the tau gene supports th e view that intronic mutations exercize their pathogenic effect by destabil izing RNA secondary structure.