title: Mutation in the tau gene in familial multiple system tauopathy with presenile dementia.
abstract: Familial multiple system tauopathy with presenile dementia (MSTD) is a neurodegenerative disease with an abundant filamentous tau protein pathology. It belongs to the group of familial frontotemporal dementias with Parkinsonism linked to chromosome 17 (FTDP-17), a major class of inherited dementing disorders whose genetic basis is unknown. We now report a G to A transition in the intron following exon 10 of the gene for microtubule-associated protein tau in familial MSTD. The mutation is located at the 3' neighboring nucleotide of the GT splice-donor site and disrupts a predicted stem-loop structure. We also report an abnormal preponderance of soluble tau protein isoforms with four microtubule-binding repeats over isoforms with three repeats in familial MSTD. This most likely accounts for our previous finding that sarkosyl-insoluble tau protein extracted from the filamentous deposits in familial MSTD consists only of tau isoforms with four repeats. These findings reveal that a departure from the normal ratio of four-repeat to three-repeat tau isoforms leads to the formation of abnormal tau filaments. The results show that dysregulation of tau protein production can cause neurodegeneration and imply that the FTDP-17 gene is the tau gene. This work has major implications for Alzheimer's disease and other tauopathies.
authors.affiliation: Medical Research Council Centre for Brain Repair and Department of Neurology, University of Cambridge, Robinson Way, Cambridge CB2 2PY, UK. mgsll@cam.ac.uk
authors.forename: M G
authors.initials: MG
authors.lastname: Spillantini
authors.forename: J R
authors.initials: JR
authors.lastname: Murrell
authors.forename: M
authors.initials: M
authors.lastname: Goedert
authors.forename: M R
authors.initials: MR
authors.lastname: Farlow
authors.forename: A
authors.initials: A
authors.lastname: Klug
authors.forename: B
authors.initials: B
authors.lastname: Ghetti
mesh_terms: D000225:Adenine; D017398:Alternative Splicing; D001483:Base Sequence; D002886:Chromosomes, Human, Pair 17; D003704:Dementia / Q000235:genetics*; D005091:Exons; D005260:Female; D006147:Guanine; D006801:Humans; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010375:Pedigree; D017354:Point Mutation; D017422:Sequence Analysis, DNA; D016875:tau Proteins / Q000235:genetics*
chemical_list: D016875:tau Proteins; D006147:Guanine; D000225:Adenine