Mutations

MAPT S305I

Overview

Pathogenicity: Other Tauopathy : Unclear Pathogenicity
Clinical Phenotype: Argyrophilic Grain Disease
Position: (GRCh38/hg38):Chr17:46010401 G>T
Position: (GRCh37/hg19):Chr17:44087767 G>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Isoform Shift; Missense
Codon Change: AGT to ATT
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10

Findings

This mutation was identified in a Hungarian individual who at the age of 39 developed behavior and personality changes. He rapidly developed progressive speech and movement disorders with cognitive impairment, depression, and anxiety. He died at age 41 with symmetric parkinsonism, vertical gaze palsy, bulbar symptoms, and severe dementia. The patient's clinical presentation and neuropathology are consistent with the sporadic tauopathy argyrophilic grain disease. Pathogenicity could not be determined, but the mutation was absent in 95 Hungarian controls (Kovacs et al., 2008).

Neuropathology

Neuropathological analysis showed extensive neuronal loss in the medial temporal cortex, hippocampus, and amygdala. Classical neurofibrillary tangles, Pick bodies, and neuritic plaques were not observed. There was evidence of diffuse cytoplasmic tau staining in neurons, coiled bodies in oligodendrocytes, and argyrophilic grains. The tau-positive structures were composed only of 4-repeat (4R) tau isoforms (Kovacs et al., 2008).

Biological Effect

This mutation affects exon 10 splicing, causing an overproduction of 4-repeat (4R) tau isoforms (Kovacs et al., 2008).

Last Updated: 18 Jul 2024

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References

Paper Citations

  1. Kovacs GG, Pittman A, Revesz T, Luk C, Lees A, Kiss E, Tariska P, Laszlo L, Molnár K, Molnar MJ, Tolnay M, de Silva R. MAPT S305I mutation: implications for argyrophilic grain disease. Acta Neuropathol. 2008 Jul;116(1):103-18. Epub 2007 Dec 8 PubMed.

Further Reading

Papers

  1. Nimsanor N, Jørring I, Rasmussen MA, Clausen C, Mau-Holzmann UA, Kitiyanant N, Nielsen JE, Nielsen TT, Hyttel P, Holst B, Schmid B. Induced pluripotent stem cells (iPSCs) derived from a symptomatic carrier of a S305I mutation in the microtubule-associated protein tau (MAPT)-gene causing frontotemporal dementia. Stem Cell Res. 2016 Oct 20;17(3):564-567. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. Kovacs GG, Pittman A, Revesz T, Luk C, Lees A, Kiss E, Tariska P, Laszlo L, Molnár K, Molnar MJ, Tolnay M, de Silva R. MAPT S305I mutation: implications for argyrophilic grain disease. Acta Neuropathol. 2008 Jul;116(1):103-18. Epub 2007 Dec 8 PubMed.

Other mutations at this position

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