Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:46010401 G>A
Position: (GRCh37/hg19):Chr17:44087767 G>A
dbSNP ID: rs63751165
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: AGT to AAT
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10

Findings

This mutation was first reported in a Japanese family affected by early onset frontotemporal dementia. The reported pedigree shows three affected individuals over two generations, with a mean onset age of 35 years. The three individuals presented first with personality changes, followed by impaired cognition and memory as well as disorientation. They later became mute. One of the three suffered from mild parkinsonism. The mutation was detected in the proband but was absent in his healthy father and maternal uncle, suggesting segregation with disease. No mutations were detected in exons 4-13 of PSEN1 or PSEN2. The S305N mutation was absent in 90 Japanese controls (Iijima et al., 1999).

In another S305N kindred, thought to be unrelated to the one described above, two mutation-carrying brothers had a clinical/pathological phenotype resembling Pick’s disease, a type of frontotemporal dementia. They initially presented with inertia and forgetfulness and had a family history consistent with familial FTD. Their paternal grandmother was known for eccentric behavior and their father died at age 44 of a syndrome characterized by behavioral changes, notably aggression. The mutation appears to segregate with disease in this family: It was present in the two affected brothers, but absent in their unaffected mother (Kobayashi et al., 2002; Kobayashi et al., 2003).

Neuropathology

Postmortem examination of the first proband revealed numerous neurofibrillary tangles with an unusual morphology and distribution. Rather than flame-shaped, the tangles appeared as ring-shaped structures frequently enveloping neuronal nuclei, especially in the frontal, temporal, insular, and postcentral cortices, as well as in dentate gyrus. Tau-positive inclusions were observed in both neurons and glia. Coiled bodies and neuropil threads resembling those seen in corticobasal degeneration were observed, and electron microscopy showed straight tubules (Iijima et al., 1999).

Neuropathological data were also available for the second kindred. MRI showed atrophy of the right temporal lobe, including the hippocampal formation. Atrophy was severe with a "knife-edge" appearance. Pick body-like inclusions were observed, including astrocytic inclusions in the hippocampus, amygdala and thalamus. Similar to the observations in the previously described kindred, electron microscopy showed straight filaments in the inclusion bodies (Kobayashi et al., 2003).

Biological Effect

In silico analyses predicted this mutation diminishes cathepsin cleavage which was confirmed in vitro using protease assays (Sampognaro et al., 2023). Consistent with these findings, the lysosomal degradation of mutant tau in neuronal-like SH-SY5Y cells was reduced.

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

1. Iijima M, Tabira T, Poorkaj P, Schellenberg GD, Trojanowski JQ, Lee VM, Schmidt ML, Takahashi K, Nabika T, Matsumoto T, Yamashita Y, Yoshioka S, Ishino H. A distinct familial presenile dementia with a novel missense mutation in the tau gene. Neuroreport. 1999 Feb 25;10(3):497-501. PubMed.
2. Kobayashi K, Hayashi M, Kidani T, Nakano H, Miyazu K, Ujike H, Kuroda S, Koshino Y. Pick's disease in 2 brothers with S305N mutation: note in supplement to an earlier communication. Clin Neuropathol. 2002 Jul-Aug;21(4):191-3. PubMed.
3. Kobayashi K, Kidani T, Ujike H, Hayashi M, Ishihara T, Miyazu K, Kuroda S, Koshino Y. Another phenotype of frontotemporal dementia and parkinsonism linked to chromosome-17 (FTDP-17) with a missense mutation of S305N closely resembling Pick's disease. J Neurol. 2003 Aug;250(8):990-2. PubMed.
4. Sampognaro PJ, Arya S, Knudsen GM, Gunderson EL, Sandoval-Perez A, Hodul M, Bowles K, Craik CS, Jacobson MP, Kao AW. Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases. Mol Neurodegener. 2023 May 2;18(1):29. PubMed. Correction.

Further Reading

Learn More

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database