A distinct familial presenile dementia with a novel missense mutation in the tau gene

Abstract

We report a Japanese family with early onset hereditary frontotemporal dementia and a novel missense mutation (Ser305Asn) in the tau gene. The patients presented with personality changes followed by impaired cognition and memory as well as disorientation, but minimal Parkinsonism. Imaging studies showed fronto-temporal atrophy with ventricular dilatation more on the left, and postmortem examination of the brain revealed numerous neurofibrillary tangles (NFTs) with an unusual morphology and distribution. Silver-stained sections showed ring-shaped NFTs partially surrounding the nucleus that were most prominent in frontal, temporal, insular and postcentral cortices, as well as in dentate gyrus. Cortical NFTs were restricted primarily to layer II, and were composed of straight tubules. Numerous glial cells containing coiled bodies and abundant neuropil threads were detected in cerebral white matter, hippocampus, basal ganglia, diencephalon and brain stem, but no senile plaques or other diagnostic lesions were seen. Both the glial and neuronal tangles were stained by antibodies to phosphorylation-independent and phosphorylation-dependent epitopes in tau. Thus, this novel mutation causes a distinct familial tauopathy.

Next Generation Sequencing Data Analysis Evaluation in Patients with Parkinsonism from a Genetically Isolated Population

“…Concerning the tau gene MAPT missense mutations p.Gly272Val, p.Asn279Lys, p.Pro301Leu, p.Pro301Ser, p.Arg406Trp, p.Gly389Arg, p.Val337Met and p.Ser305Asn were found in the patients with frontotemporal dementia type of Parkinsonism [29][30][31][32][33][34][35][36][37]. The substitution mutation (rs63750072; p.Gln230Arg) found in our study exchanges uncharged polar amino acids for alkaline in MAPT gene.…”

Aberrant Splicing of tau Pre-mRNA Caused by Intronic Mutations Associated with the Inherited Dementia Frontotemporal Dementia with Parkinsonism Linked to Chromosome 17

“…The brain atrophy is usually accompanied by neuronal cell death, gliosis, and formation of intraneuronal deposits containing tau protein. Missense mutations in the tau gene have been identified in FTDP-17 cases, and several of these mutations lead to a reduction in the ability of tau to bind MT and to promote MT assembly (24,(29)(30)(31)50). In addition to mutations found in the coding region of the tau gene, several intronic mutations were identified, accounting for a significant fraction of FTDP-17 cases (Fig.…”

Astrogliopathy in Tauopathies

“…Various types of astrocytic inclusions are generated in familial FTLD-tau linked to mutations in exons 1 and 10 and in introns following exons 9 and 10, the morphology of which largely depends on the MAPT mutation. Intracytoplasmic tau-immunoreactive inclusions in FTLD-tau are represented by tufted-like astrocytes, astrocytic plaques, ramified astrocytes, TSAs, astrocytes with globular inclusions and other types with no specific names [17,33,34,36,37,66,[77][78][79][80][81][82][83][84][85][86]. Tufted astrocytes and astrocytic plaques practically do not co-exist in PSP and CBD [57], but these lesions appear in combination in FTLD-tau [29] (Figure 4).…”