title: A MAPT mutation in a regulatory element upstream of exon 10 causes frontotemporal dementia.
abstract: 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. This finding supports earlier studies on the effect of a splice-accepting element 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.
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, Porter Neuroscience Building, 35, Convent Drive, Bethesda, MD 20892, USA.
authors.forename: Roneil
authors.initials: R
authors.lastname: Malkani
authors.forename: Ian
authors.initials: I
authors.lastname: D'Souza
authors.forename: Katrina
authors.initials: K
authors.lastname: Gwinn-Hardy
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Schellenberg
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Parastoo
authors.initials: P
authors.lastname: Momeni
mesh_terms: D000818:Animals; D004252:DNA Mutational Analysis; D003704:Dementia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D018450:Disease Progression; D005091:Exons / Q000235:genetics*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016716:PC12 Cells; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics; D051381:Rats; D050436:Regulatory Elements, Transcriptional / Q000235:genetics*; D013702:Temporal Lobe / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016875:tau Proteins
chemical_list: C054369:MAPT protein, human; D009419:Nerve Tissue Proteins; D022821:RNA Splice Sites; D016875:tau Proteins