P3-157: A MAPT mutation in a regulatory element upstream of exon 10 causes frontotemporal dementia

Abstract

Mutations in the MAPT tau gene are a major cause of frontotemporal dementia. Mutations described in this gene to date have either been coding changes or mutations in exon 10 or in intron 10 which alter the splicing of this exon such that a greater proportion of the tau transcript contains this exon. We report here the genetic analysis of a newly ascertained kindred in which frontotemporal dementia occurs in an apparent autosomal dominant fashion, and in which a novel MAPT gene mutation co–segregates with disease. Sequencing the MAPT gene in affected individuals revealed a change in intron 9 g(–10)t. This finding supports earlier studies in which the effect of a splice–accepting element results in inclusion of exon 10 in the MAPT transcript. This mutation sheds light on a novel mechanism by which over–expression of 4–repeat tau leads to disease. Based on our current findings we propose a novel mechanism by which intronic mutations can lead to frontotemporal dementia.