Mutations

MAPT N279K

Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Genome Build: 105
Position: Chr17:44087690 T>G
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 progressive supranuclear palsy. Individuals with the N279K mutation typically have a parkinsonism-predominant phenotype. Personality changes, behavioral changes, and dementia also occur, but they are generally less prominent and/or seen later in the course of the disease (Tsuboi et al., 2002).

One large N279K 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. In this family, symptom onset and death consistently occurred in the fifth decade (Wszolek et al., 1992).

The N279K mutation has also been identified in at least three Japanese families with clinical syndromes resembling PSP (Ogaki et al., 2011Ogaki et al., 2012). In the largest of these families, family B, the reported pedigree indicates nine individuals over three generations affected by parkinsonism (n=7) or dementia with parkinsonism (n=2). The N279K mutation appeared to segregate with disease in this family; it was present in three affected carriers (two with dementia with parkinsonism, one with parkinsonism without dementia) and was absent in an unaffected relative. Onset in this family ranged from 42 to 46 years of age, with parkinsonism as the initial symptom in all three cases. Symptoms included bradykinesia, rigidity, postural tremors, gaze palsy, and motor impairments.

In another Japanese family, family D, two sisters were affected by PSP, with onset at 42 and 43 years of age, respectively. In both cases, parkinsonism was the initial symptom and they exhibited supranuclear gaze palsy, bradykinesia, rigidity, postural instability, and visual grasping, a fixed gaze on a random object in the environment. The sisters died at age 54 and 51, respectively (Ogaki et al., 2011Ogaki et al., 2012).

Another Japanese woman, not known to be genealogically connected to the previously described families, developed PSP symptoms at the age of 41 and died 10 years later. She presented first with parkinsonism, and like the two sisters described above, developed supranuclear gaze palsy, bradykinesia, rigidity, postural instability, and visual grasping (Ogaki et al., 2011Ogaki et al., 2012).

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). Although tau tangles are not typical, other types of tau inclusions have been described in neurons and glia in a variety of brain regions including the cortex, basal ganglia, brain stem nuclei, and white matter. Inclusions consisted primarily of four repeat (4R), not three-repeat (3R), isoforms of tau, consistent with PSP (Delisle et al., 1999; Ogaki et al., 2012). In some cases, 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 and hence more 4R tau protein (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. . Visual grasping in frontotemporal dementia and parkinsonism linked to chromosome 17 (microtubule-associated with protein tau): a comparison of N-Isopropyl-p-[(123)I]-iodoamphetamine brain perfusion single photon emission computed tomography analysis with . Mov Disord. 2011 Feb 15;26(3):561-3. PubMed.
  4. . Analyses of the MAPT, PGRN, and C9orf72 mutations in Japanese patients with FTLD, PSP, and CBS. Parkinsonism Relat Disord. 2012 Jul 18; PubMed.
  5. . 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.
  6. . 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.
  12. . 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.

Learn More

  1. Japanese Familial Alzheimer's Disease Database

Primary Papers

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

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