title: A novel mutation at position +12 in the intron following exon 10 of the tau gene in familial frontotemporal dementia (FTD-Kumamoto)
abstract: Exonic and intronic mutations in the tau gene cause familial 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 frontotemporal dementia. The mutation caused a marked reduction in melting temperature of the tau exon 10-splicing regulatory element RNA and a large increase in exon 10-containing transcripts. Brain tissue from affected individuals showed an abnormal preponderance of exon 10-containing transcripts that was reflected at the protein level by an overproduction of tau isoforms with four microtubule-binding repeats. Immunostaining revealed the presence of tau aggregates in degenerating neurons and glial cells. Isolated tau filaments had a twisted ribbon-like morphology and were made of hyperphosphorylated four-repeat tau isoforms. The additional mutation located dose to the splice-donor site of the intron following exon 10 of the tau gene supports the view that intronic mutations exercize their pathogenic effect by destabilizing RNA secondary structure.
authors.affiliation: Hyogo Institute for Aging Brain and Cognitive Disorders, Himeji, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yasuda
authors.forename: J
authors.initials: J
authors.lastname: Takamatsu
authors.forename: I
authors.initials: I
authors.lastname: D'Souza
authors.forename: R A
authors.initials: RA
authors.lastname: Crowther
authors.forename: T
authors.initials: T
authors.lastname: Kawamata
authors.forename: M
authors.initials: M
authors.lastname: Hasegawa
authors.forename: H
authors.initials: H
authors.lastname: Hasegawa
authors.forename: M G
authors.initials: MG
authors.lastname: Spillantini
authors.forename: S
authors.initials: S
authors.lastname: Tanimukai
authors.forename: P
authors.initials: P
authors.lastname: Poorkaj
authors.forename: L
authors.initials: L
authors.lastname: Varani
authors.forename: G
authors.initials: G
authors.lastname: Varani
authors.forename: T
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: M
authors.initials: M
authors.lastname: Goedert
authors.forename: D G
authors.initials: DG
authors.lastname: Schellenberg
authors.forename: C
authors.initials: C
authors.lastname: Tanaka
mesh_terms: D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D003704:Dementia / Q000235:genetics* / Q000473:pathology; D003902:Detergents; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D006358:Hot Temperature; D006801:Humans; D007438:Introns / Q000235:genetics*; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D010375:Pedigree; D017354:Point Mutation; D012326:RNA Splicing / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D012521:Sarcosine / Q000031:analogs & derivatives; D012995:Solubility; D016875:tau Proteins / Q000032:analysis / Q000235:genetics* / Q000648:ultrastructure
chemical_list: D003902:Detergents; D012333:RNA, Messenger; D016875:tau Proteins; C025231:sarkosyl; D012521:Sarcosine