Mutations

MAPT P301L

Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Genomic Mutation Name (MET1): g.123790C>T
Genomic Mutation Name (NT1): g.120969C>T
dbSNP ID: rs63751273
Coding/Non-Coding: Coding
Genomic Region: Exon 10
Mutation Type: Point, Missense
Codon Change: CCG to CTG
Research Models: 6

Findings

Originally identified in a Dutch kindred (hereditary frontal temporal dementia (HFTD1), a U.S. kindred (FTD003) (Hutton et al., 1998), and in six French families diagnosed with FTDP (Dumanchin et al., 1998), the P301L mutation has since been identified in approximately 32 families around the world. The mutation occurs in a highly conserved region of the tau sequence within exon 10 and only affects the 4-repeat (4R) tau isoforms because exon 10 is spliced out of 3-repeat (3R) isoforms.

Neuropathology

Tau aggregates in the brains of affected individuals consist mainly of 4-repeat (4R) isoforms (Hutton et al., 1998). A detailed histopathological analysis of the Dutch kindred (HFTD1) found numerous intracytoplasmic tau deposits in neurons and glia in multiple brain regions including the hippocampus, neocortex, and substantia nigra. Severe neuronal loss, gliosis, and a few ballooned cells were observed in the frontal and temporal cortices (Spillantini et al., 1998).

Biological Effect

In vitro, this mutation has been shown to accelerate the formation of paired helical filaments (Barghorn et al., 2000). It also strongly promotes β-sheet formation during aggregation (von Bergen et al., 2001; Fischer et al., 2007). The P301L mutation is not associated with a change in exon 10 splicing.

Research Models

Many mouse models carrying this human mutation have been generated, including the widely used triple transgenic 3xTg, the single transgenic JNPL3, and the conditional line rTg(tauP301L)4510.

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References

Research Models Citations

  1. 3xTg
  2. JNPL3(P301L)
  3. rTg(tauP301L)4510

Paper Citations

  1. . Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998 Jun 18;393(6686):702-5. PubMed.
  2. . Segregation of a missense mutation in the microtubule-associated protein tau gene with familial frontotemporal dementia and parkinsonism. Hum Mol Genet. 1998 Oct;7(11):1825-9. PubMed.
  3. . Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau. Am J Pathol. 1998 Nov;153(5):1359-63. PubMed.
  4. . Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry. 2000 Sep 26;39(38):11714-21. PubMed.
  5. . Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure. J Biol Chem. 2001 Dec 21;276(51):48165-74. PubMed.
  6. . Structural and microtubule binding properties of tau mutants of frontotemporal dementias. Biochemistry. 2007 Mar 13;46(10):2574-82. PubMed.

Further Reading

Papers

  1. . A clinical pathological comparison of three families with frontotemporal dementia and identical mutations in the tau gene (P301L). Brain. 1999 Apr;122 ( Pt 4):741-56. PubMed.
  2. . Tau pathology in a family with dementia and a P301L mutation in tau. J Neuropathol Exp Neurol. 1999 Apr;58(4):335-45. PubMed.
  3. . From genotype to phenotype: a clinical pathological, and biochemical investigation of frontotemporal dementia and parkinsonism (FTDP-17) caused by the P301L tau mutation. Ann Neurol. 1999 Jun;45(6):704-15. PubMed.
  4. . Familial frontotemporal dementia with a P301L tau mutation in Japan. J Neurol Sci. 2000 Feb 1;176(1) PubMed.
  5. . A case of frontotemporal dementia with tau P301L mutation in the Far East. J Neurol. 2000 Sep;247(9):705-7. PubMed.
  6. . Mutation-dependent aggregation of tau protein and its selective depletion from the soluble fraction in brain of P301L FTDP-17 patients. Hum Mol Genet. 2000 Dec 12;9(20):3075-82. PubMed.
  7. . Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia. Arch Neurol. 2001 Mar;58(3):383-7. PubMed.
  8. . Total tau and phosphorylated tau 181 levels in the cerebrospinal fluid of patients with frontotemporal dementia due to P301L and G272V tau mutations. Arch Neurol. 2003 Sep;60(9):1209-13. PubMed.
  9. . Interaction between tau and alpha-synuclein proteins is impaired in the presence of P301L tau mutation. Exp Cell Res. 2005 Aug 1;308(1):78-84. PubMed.
  10. Abstracts of the Sixteenth Meeting of the European Neurological Society. May 27-31, 2006. Lausanne, Switzerland. J Neurol. 2006 May 01;253 Suppl 2:II3-159. PubMed.
  11. . Clinicopathological and genetic correlates of frontotemporal lobar degeneration and corticobasal degeneration. J Neurol. 2008 Apr;255(4):488-94. PubMed.

Learn More

Alzheimer Disease & Frontotemporal Dementia Mutation Database

Primary Papers

  1. . Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998 Jun 18;393(6686):702-5. PubMed.
  2. . Segregation of a missense mutation in the microtubule-associated protein tau gene with familial frontotemporal dementia and parkinsonism. Hum Mol Genet. 1998 Oct;7(11):1825-9. PubMed.
  3. . Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13103-7. PubMed.
  4. . Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau. Am J Pathol. 1998 Nov;153(5):1359-63. PubMed.

Other mutations at this position

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