Compound heterozygosity of 2 novel MAPT mutations in frontotemporal dementia

• Published in: Neurobiology of aging Vol. 32; no. 4; pp. 757.e1 - 757.e11
• Main Authors: Anfossi, Maria, Vuono, Romina, Maletta, Raffaele, Virdee, Kanwar, Mirabelli, Maria, Colao, Rosanna, Puccio, Gianfranco, Bernardi, Livia, Frangipane, Francesca, Gallo, Maura, Geracitano, Silvana, Tomaino, Carmine, Curcio, Sabrina Anna Maria, Zannino, Giuseppa, Lamenza, Francesco, Duyckaerts, Charles, Spillantini, Maria Grazia, Losso, Maria Adele, Bruni, Amalia C
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2011
• Subjects: 3Rtau isoforms; Blotting, Western; Brain - metabolism; Brain - pathology; Female; Frontotemporal Dementia - diagnosis; Frontotemporal Dementia - genetics; Frontotemporal Dementia - metabolism; Humans; Immunohistochemistry; Internal Medicine; Introns; Magnetic Resonance Imaging; MAPT gene; Middle Aged; Mutation; Neurodegeneration; Neurology; Neuropsychological Tests; Novel intronic mutations; Pick's disease; tau Proteins - genetics; tau Proteins - metabolism; Pick's disease; Novel intronic mutations; MAPT gene; Neurodegeneration; 3Rtau isoforms
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2010.12.013

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.