Mutations

MAPT P301L

Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Reference Assembly: GRCh37/hg19
Position: Chr17:44087755 C>T
dbSNP ID: rs63751273
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCG to CTG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10
Research Models: 10

Findings

Originally identified in a Dutch kindred (HFTD1), a U.S. kindred (FTD003) (Hutton et al., 1998), and in six French families diagnosed with frontotemporal dementia and parkinsonism (Dumanchin et al., 1998), the P301L mutation has since been found 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 4R isoforms (Hutton et al., 1998). A detailed histopathological analysis of 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.

Last Updated: 05 Jun 2013

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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 May 1;176(1):57-64. 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;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. Epub 2008 Mar 25 PubMed.
  12. . High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am J Hum Genet. 1999 Feb;64(2):414-21. PubMed.
  13. . Accelerated filament formation from tau protein with specific FTDP-17 missense mutations. FEBS Lett. 1999 Mar 26;447(2-3):195-9. PubMed.
  14. . The apolipoprotein E epsilon4 allele is not a significant risk factor for frontotemporal dementia. Ann Neurol. 1998 Jul;44(1):134-8. PubMed.
  15. . Frequency of tau mutations in three series of non-Alzheimer's degenerative dementia. Ann Neurol. 1999 Aug;46(2):243-8. PubMed.
  16. . Phenotypic variation in hereditary frontotemporal dementia with tau mutations. Ann Neurol. 1999 Oct;46(4):617-26. PubMed.
  17. . Genetic analysis in patients with familial and sporadic frontotemporal dementia: two tau mutations in only familial cases and no association with apolipoprotein epsilon4. Dement Geriatr Cogn Disord. 2001 Nov-Dec;12(6):387-92. PubMed.
  18. . Contrasting genotypes of the tau gene in two phenotypically distinct patients with P301L mutation of frontotemporal dementia and parkinsonism linked to chromosome 17. J Neurol. 2002 Jun;249(6):669-75. PubMed.
  19. . A family with a tau P301L mutation presenting with parkinsonism. Parkinsonism Relat Disord. 2002 Dec;9(2):121-3. PubMed.
  20. . Prevalence of TAU mutations in an Italian clinical series of familial frontotemporal patients. Neurosci Lett. 2003 Feb 20;338(1):85-7. PubMed.
  21. . Novel tau polymorphisms, tau haplotypes, and splicing in familial and sporadic frontotemporal dementia. Arch Neurol. 2003 May;60(5):698-702. PubMed.
  22. . Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain. 2003 Sep;126(Pt 9):2016-22. Epub 2003 Jul 22 PubMed.
  23. . Frequency of tau mutations in familial and sporadic frontotemporal dementia and other tauopathies. J Neurol. 2004 Sep;251(9):1098-104. PubMed.
  24. Abstracts of the Sixteenth Meeting of the European Neurological Society. May 27-31, 2006. Lausanne, Switzerland. J Neurol. 2006 May;253 Suppl 2:II3-159. PubMed.
  25. . Mutations in progranulin gene: clinical, pathological, and ribonucleic acid expression findings. Biol Psychiatry. 2008 May 15;63(10):946-52. Epub 2007 Oct 22 PubMed.
  26. . A mechanistic model of tau amyloid aggregation based on direct observation of oligomers. Nat Commun. 2015 Apr 30;6:7025. PubMed.
  27. . Generation of an isogenic, gene-corrected iPSC line from a symptomatic 57-year-old female patient with frontotemporal dementia caused by a P301L mutation in the microtubule associated protein tau (MAPT) gene. Stem Cell Res. 2016 Sep 28;17(3):556-559. PubMed.

Learn More

  1. Alzheimer Disease & Frontotemporal Dementia Mutation Database

Protein Diagram

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.

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