Mutations

MAPT N279K

Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Genomic Mutation Name (MET1):
Genomic Mutation Name (NT1):
dbSNP ID: rs63750756
Coding/Non-Coding: Coding
Genomic Region: Exon 10
Mutation Type: Point, Missense
Codon Change: AAT to AAG

Findings

This mutation has been identified in at least seven families across the globe. Phenotypic presentation varies, but generally affected individuals develop symptoms of dementia, parkinsonism, and supranuclear palsy. Individuals with the N279K mutation typically have a parkinsonism-predominant phenotype. Although personality changes, behavioral changes, and dementia also occur, they are less prominent and/or seen later in the course of the disease (Tsuboi et al., 2002).

One large kindred involving more than 32 affected people across eight generations developed a particularly aggressive form of disease characterized by progressive parkinsonism with dystonia, dementia, ocular motility abnormalities, pyramidal tract dysfunction, frontal lobe release signs, perseverative vocalizations, and urinary incontinence. The course of disease in this family was very aggressive, with symptom onset and death consistently in the fifth decade (Wszolek et al., 1992).

Neuropathology

Autopsy findings revealed severe neuronal loss with gliosis in the substantia nigra, pontine tegmentum, and globus pallidus, with some loss also in the caudate and putamen. Notably absent were plaques, tangles, Lewy bodies, and amyloid bodies (Wszolek et al., 1992). However, another study observed widespread neuronal and glial tau accumulation in the cortex, basal ganglia, brain stem nuclei, and white matter (Delisle et al., 1999). Tau isolated from the insoluble fraction is primarily 4-repeat (4R). Substantial tau deposition was also observed in the medial temporal cortices and upper and lower motor neurons with accompanying corticospinal tract degeneration (Arima et al., 2000).

Biological Effect

The N279K mutation affects splicing similar to many intronic mutations in MAPT, resulting in more frequent incorporation of exon 10 into tau transcripts (Delisle et al., 1999).

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References

Paper Citations

  1. . Clinical features and disease haplotypes of individuals with the N279K tau gene mutation: a comparison of the pallidopontonigral degeneration kindred and a French family. Arch Neurol. 2002 Jun;59(6):943-50. PubMed.
  2. . Rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration. Ann Neurol. 1992 Sep;32(3):312-20. PubMed.
  3. . A mutation at codon 279 (N279K) in exon 10 of the Tau gene causes a tauopathy with dementia and supranuclear palsy. Acta Neuropathol. 1999 Jul;98(1):62-77. PubMed.
  4. . Two brothers with frontotemporal dementia and parkinsonism with an N279K mutation of the tau gene. Neurology. 2000 May 9;54(9):1787-95. PubMed.

Further Reading

Papers

  1. . Pallidonigroluysian degeneration with iron deposition: a study of three autopsy cases. Acta Neuropathol. 1993;86(6):609-16. PubMed.
  2. . Clinical features and disease haplotypes of individuals with the N279K tau gene mutation: a comparison of the pallidopontonigral degeneration kindred and a French family. Arch Neurol. 2002 Jun;59(6):943-50. PubMed.
  3. . Interest in genetic testing in pallido-ponto-nigral degeneration (PPND): a family with frontotemporal dementia with Parkinsonism linked to chromosome 17. Eur J Neurol. 2001 Mar;8(2):179-83. PubMed.
  4. . Physiologic assessment of autonomic dysfunction in pallidopontonigral degeneration with N279K mutation in the tau gene on chromosome 17. Auton Neurosci. 2002 Nov 29;102(1-2):71-7. PubMed.
  5. . Two brothers with frontotemporal dementia and parkinsonism with an N279K mutation of the tau gene. Neurology. 2000 May 9;54(9):1787-95. PubMed.
  6. . A mutation in the microtubule-associated protein tau in pallido-nigro-luysian degeneration. Neurology. 1999 Sep 11;53(4):864-8. PubMed.
  7. . A mutation at codon 279 (N279K) in exon 10 of the Tau gene causes a tauopathy with dementia and supranuclear palsy. Acta Neuropathol. 1999 Jul;98(1):62-77. PubMed.
  8. . 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.
  9. . Clinical and genetic studies of families with the tau N279K mutation (FTDP-17). Neurology. 2002 Dec 10;59(11):1791-3. PubMed.
  10. . Clinical neurophysiologic findings in patients with rapidly progressive familial parkinsonism and dementia with pallido-ponto-nigral degeneration. Electroencephalogr Clin Neurophysiol. 1998 Sep;107(3):213-22. PubMed.
  11. . The neuropathology of a chromosome 17-linked autosomal dominant parkinsonism and dementia ("pallido-ponto-nigral degeneration"). J Neuropathol Exp Neurol. 1998 Jun;57(6):588-601. PubMed.

Learn More

Primary Papers

  1. . Rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration. Ann Neurol. 1992 Sep;32(3):312-20. PubMed.