Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic, Other Tauopathy : Pathogenic
Clinical Phenotype: Frontotemporal Dementia, Progressive Supranuclear Palsy
Position: (GRCh38/hg38):Chr17:46010402 T>C
Position: (GRCh37/hg19):Chr17:44087768 T>C
dbSNP ID: rs63750568
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift; Silent
Codon Change: AGT to AGC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10

Findings

Clinical and pathological variations of the S305S mutation are seen in carriers both within and between families. The mutation has been linked to autosomal frontotemporal dementia (Skoglund et al., 2008) and to progressive supranuclear palsy (Stanford et al., 2000). In one kindred, three affected family members showed alterations in personality and behavior, as well as cognitive decline and late levodopa-resistant parkinsonian symptoms, consistent with the diagnosis of FTD. Neuropathologically, the one autopsied case displayed degeneration of the frontal and temporal lobes together with extensive tau pathology in both neurons and glia. Increased levels of 4-repeat (4R) tau were also observed compared with 3-repeat (3R) tau (Skoglund et al., 2008). In another kindred, two affected sisters had different clinical presentations and neuropathology. One had clinically and neuropathologically confirmed progressive supranuclear palsy without dementia (Stanford et al., 2000), while the other sister's clinical and neuropathological features were more consistent with a diagnosis of FTDP-17 (Halliday et al., 2006).

Neuropathology

Neuropathology varies even within families. In one family with two affected sisters, one was diagnosed with progressive supranuclear palsy and had silver-positive neurofibrillary tangles, while the other sister did not meet clinical criteria for PSP and postmortem analysis suggested FTDP-17. Her brain showed mild atrophy in the frontal and temporal lobes associated with cell loss and gliosis and silver-negative, tau-positive neurons. Tufted astrocytes, astrocytic plaques, and ballooned neurons were also observed throughout the cortex (Halliday et al., 2006).

Biological Effect

This silent mutation increases the splicing in of exon 10 and results in overproduction of tau isoforms containing four repeats (4R).

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References

Paper Citations

1. Skoglund L, Viitanen M, Kalimo H, Lannfelt L, Jönhagen ME, Ingelsson M, Glaser A, Herva R. The tau S305S mutation causes frontotemporal dementia with parkinsonism. Eur J Neurol. 2008 Feb;15(2):156-61. Epub 2007 Dec 18 PubMed.
2. Stanford PM, Halliday GM, Brooks WS, Kwok JB, Storey CE, Creasey H, Morris JG, Fulham MJ, Schofield PR. Progressive supranuclear palsy pathology caused by a novel silent mutation in exon 10 of the tau gene: expansion of the disease phenotype caused by tau gene mutations. Brain. 2000 May;123 ( Pt 5):880-93. PubMed.
3. Halliday GM, Song YJ, Creasey H, Morris JG, Brooks WS, Kril JJ. Neuropathology in the S305S tau gene mutation. Brain. 2006 Mar;129(Pt 3):E40. PubMed.

Further Reading

Learn More

1. Alzheimer Disease & Frontotemporal Dementia Mutation Database