title: Compound heterozygosity of 2 novel MAPT mutations in frontotemporal dementia.
abstract: Intronic MAPT mutations altering exon 10 splicing lead mainly to an increase of 4Rtau. The objective of this study is to report clinical, genetic, and neuropathological data of an apparently sporadic early onset frontotemporal dementia (FTD) case associated with 2 novel intronic MAPT gene mutations IVS10+4A > C and IVS9-15T > C that increase 3Rtau. Methods and subjects used are clinical, neuroradiological, and neuropathological examination; molecular genetics of MAPT, PGRN, and other relevant genes. Exon 10 splicing tested with minigene constructs. Tau deposits detected by immunohistochemistry. Sarkosyl-insoluble and soluble tau investigated by immunoblotting. Two novel MAPT mutations IVS10+4A > C and the IVS9-15T > C transmitted by the unaffected parents were identified. Semiquantitative reverse transcription polymerase chain reaction (RT-PCR) analyses on minigenes and in brain tissue showed that both mutations cause an increase of tau mRNA (messenger ribonucleic acid) transcripts lacking exon 10 only in the patient. Immunohistochemistry and immunoblotting of the patient's brain revealed tau deposits composed mostly of 3Rtau isoforms with a predominance of the shorter 3Rtau isoforms. The compound heterozygosity of the patient increasing 3Rtau seems to be responsible for the disease and furthermore suggests that sporadic cases can be caused by genetic mutations.
authors.affiliation: Regional Neurogenetic Centre, ASP Catanzaro, Lamezia Terme (CZ), Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Anfossi
authors.forename: Romina
authors.initials: R
authors.lastname: Vuono
authors.forename: Raffaele
authors.initials: R
authors.lastname: Maletta
authors.forename: Kanwar
authors.initials: K
authors.lastname: Virdee
authors.forename: Maria
authors.initials: M
authors.lastname: Mirabelli
authors.forename: Rosanna
authors.initials: R
authors.lastname: Colao
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Puccio
authors.forename: Livia
authors.initials: L
authors.lastname: Bernardi
authors.forename: Francesca
authors.initials: F
authors.lastname: Frangipane
authors.forename: Maura
authors.initials: M
authors.lastname: Gallo
authors.forename: Silvana
authors.initials: S
authors.lastname: Geracitano
authors.forename: Carmine
authors.initials: C
authors.lastname: Tomaino
authors.forename: Sabrina Anna Maria
authors.initials: SA
authors.lastname: Curcio
authors.forename: Giuseppa
authors.initials: G
authors.lastname: Zannino
authors.forename: Francesco
authors.initials: F
authors.lastname: Lamenza
authors.forename: Charles
authors.initials: C
authors.lastname: Duyckaerts
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Spillantini
authors.forename: Maria Adele
authors.initials: MA
authors.lastname: Losso
authors.forename: Amalia C
authors.initials: AC
authors.lastname: Bruni
mesh_terms: D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D005260:Female; D057180:Frontotemporal Dementia / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007438:Introns; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009154:Mutation; D009483:Neuropsychological Tests; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins