Mutations

MAPT S305N

Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Reference Assembly: GRCh37 (105)
Position: Chr17:44087767 G>A
dbSNP ID: rs63751165
Coding/Non-Coding: Coding
Mutation Type: Point, 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., 2002Kobayashi 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

Unknown.

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References

Paper Citations

  1. . A distinct familial presenile dementia with a novel missense mutation in the tau gene. Neuroreport. 1999 Feb 25;10(3):497-501. PubMed.
  2. . 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. . 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.

Further Reading

Papers

  1. . KP1 expression of ghost Pick bodies, amyloid P-positive astrocytes and selective nigral degeneration in early onset Picks disease. Clin Neuropathol. 1999 Sep-Oct;18(5):240-9. PubMed.
  2. . Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia. Arch Neurol. 2001 Mar;58(3):383-7. PubMed.
  3. . Pick's disease pathology of a missense mutation of S305N of frontotemporal dementia and parkinsonism linked to chromosome 17: another phenotype of S305N. Dement Geriatr Cogn Disord. 2004;17(4):293-7. PubMed.
  4. . Longitudinal characterization of two siblings with frontotemporal dementia and parkinsonism linked to chromosome 17 associated with the S305N tau mutation. Brain. 2005 Apr;128(Pt 4):752-72. Epub 2004 Dec 22 PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

Primary Papers

  1. . A distinct familial presenile dementia with a novel missense mutation in the tau gene. Neuroreport. 1999 Feb 25;10(3):497-501. PubMed.
  2. . 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.

Other mutations at this position

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