A heterozygous splicing variant IVS9-7A > T in intron 9 of the MAPT gene in a patient with right-temporal variant frontotemporal dementia with atypical 4 repeat tauopathy

• Published in: Acta neuropathologica communications 2023-08, Vol.11 (1), p.130-130, Article 130
• Main Authors: Mori, Kohji, Shigenobu, Kazue, Beck, Goichi, Uozumi, Ryota, Satake, Yuto, Suzuki, Maki, Kondo, Shizuko, Gotoh, Shiho, Yonenobu, Yuki, Kawai, Makiko, Suzuki, Yuki, Saito, Yuko, Morii, Eiichi, Hasegawa, Masato, Mochizuki, Hideki, Murayama, Shigeo, Ikeda, Manabu
• Format: Article
• Language: English
• Subjects: Age; Alzheimer's disease; Aphasia; Atrophy; Behavioral variant frontotemporal dementia; Brain research; Case Report; Dementia; Eating behavior; Frontotemporal lobar degeneration; Genetic research; Intron; MAPT; Memory; Mutation; Neuropathology; Neuropsychology; Pathology; Psychiatrists; Right-temporal variant frontotemporal dementia; Semantics; Splicing
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-023-01629-3

Right temporal variant frontotemporal dementia, also called right-predominant semantic dementia, often has an unclear position within the framework of the updated diagnostic criteria for behavioral variant frontotemporal dementia or primary progressive aphasia. Recent studies have suggested that this population may be clinically, neuropathologically, and genetically distinct from those with behavioral variant frontotemporal dementia or left-predominant typical semantic variant primary progressive aphasia. Here we describe a Japanese case of right temporal variant frontotemporal dementia with novel heterozygous MAPT mutation Adenine to Thymidine in intervening sequence (IVS) 9 at position -7 from 3' splicing site of intron 9/exon 10 boundary (MAPT IVS9-7A > T). Postmortem neuropathological analysis revealed a predominant accumulation of 4 repeat tau, especially in the temporal lobe, amygdala, and substantia nigra, but lacked astrocytic plaques or tufted astrocytes. Immunoelectron microscopy of the tau filaments extracted from the brain revealed a ribbon-like structure. Moreover, a cellular MAPT splicing assay confirmed that this novel variant promoted the inclusion of exon 10, resulting in the predominant production of 4 repeat tau. These data strongly suggest that the MAPT IVS9-7 A > T variant found in our case is a novel mutation that stimulates the inclusion of exon 10 through alternative splicing of MAPT transcript and causes predominant 4 repeat tauopathy which clinically presents as right temporal variant frontotemporal dementia.